235 results on '"Andrew G Hendrickx"'
Search Results
2. Serum Leptin in Nonpregnant and Pregnant Women and in Old and New World Nonhuman Primates
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V. Daniel Castracane, Michael C. Henson, and Andrew G Hendrickx
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Leptin ,Primates ,0301 basic medicine ,medicine.medical_specialty ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Internal medicine ,medicine ,Animals ,Humans ,Saimiri ,Fetus ,business.industry ,Trophoblast ,medicine.disease ,Macaca mulatta ,Macaca fascicularis ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,030220 oncology & carcinogenesis ,Serum leptin ,Female ,business ,Papio ,Hormone - Abstract
Leptin is a hormone that is produced during mammalian pregnancy in the placental trophoblast and other tissues, including! fetal and maternal adipocytes. Synthesis of the polypeptide and the presence of its specific receptors throughout the human maternal fetoplacental unit suggest direct effects on conceptus growth and development. However, both the physiologic roles of leptin and the mechanisms regulating leptin synthesis in human pregnancy differ from those in laboratory and domestic species, necessitating the development of nonhuman primate research models. Therefore, we compared serum leptin concentrations in nonpregnant and pregnant women with those in both old world nonhuman primates (i.e., baboon, rhesus monkey, cynomolgus monkey) and new world nonhuman primates (i.e., squirrel monkey, titi monkey). As expected, maternal leptin levels were elevated in human and baboon pregnancies (P < 0.05 and P < 0.001, respectively). Levels in both species of old world monkeys were also greatly enhanced (P < 0.001). Although maternal serum concentrations were slightly elevated compared to nonpregnant levels in both species of new world monkeys, overall concentrations were dramatically lower than for either old world primates or humans. Results provide comparisons of serum leptin concentrations in pregnant and nonpregnant humans and baboons with those in both old and new world monkeys and further characterize these nonhuman primates as models for the investigation of leptin dynamics in pregnancy.
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- 2005
3. The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on chorionic gonadotrophin activity in pregnant macaques
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Kala Natarajan, Jiangang Chen, Bill L. Lasley, Andrew G Hendrickx, James W. Overstreet, and Lisa S. Laughlin
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medicine.medical_specialty ,Polychlorinated Dibenzodioxins ,Apoptosis ,Biology ,Toxicology ,Chorionic Gonadotropin ,Mice ,Pregnancy ,Internal medicine ,Placenta ,medicine ,Animals ,Humans ,Conceptus ,Blastocyst ,Cells, Cultured ,reproductive and urinary physiology ,Fetus ,Trophoblast ,Embryo, Mammalian ,medicine.disease ,Immunohistochemistry ,Macaca fascicularis ,Teratogens ,medicine.anatomical_structure ,Endocrinology ,Toxicity ,Gestation ,Female ,Follicle Stimulating Hormone - Abstract
As many as 62% of all human conceptions are lost prior to 12 weeks of pregnancy and it is unknown how many of these losses result from environmental hazards. Previous studies have shown that single doses of 1, 2, and 4 microg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) administrated orally to cynomolgus macaques during the peri-implantation period leads to early fetal loss (EFL) within 10-20 days. TCDD induced EFL is associated with a reduction in the biological activity of monkey chorionic gonadotrophin (mCG) but no change in the immunoreactive mCG profile. These studies are consistent with either a direct effect of TCDD on differentiation of the trophoblast and an indirect effect on mCG synthesis, or a direct effect on mCG synthesis and secretion independent of trophoblast development. The present study was designed to test the hypothesis that the action of TCDD is directly on mCG synthesis rather than on the differentiation of the trophoblast. Female macaques (Macaca fascicularis) were treated with a single dose of TCDD (4 microg/kg b.wt.) on Gestational Day 20, a stage of pregnancy following initial trophoblast differentiation and invasion. Circulating mCG concentrations were monitored for the next 6 days. Compared to the controls, the peak level of serum bioactive mCG was lower in the treated group (P
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- 2003
4. Development of the Upper Lip
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Andrew G Hendrickx, Erik C. Peterson, Craig W. Senders, and Mark A. Cukierski
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business.industry ,Gestational Age ,Observation ,Medial nasal prominence ,General Medicine ,Anatomy ,Lip ,Solar prominence ,Maxillary prominence ,Frontonasal prominence ,Macaca fascicularis ,stomatognathic diseases ,medicine.anatomical_structure ,Face ,Maxilla ,Models, Animal ,Microscopy, Electron, Scanning ,medicine ,Animals ,Surgery ,business ,Process (anatomy) ,Nose ,Lateral nasal prominence - Abstract
Objectives: To affirm and reanalyze George L. Streeter’s “mergingtheory”ofupper-lipdevelopmentinprimatesby observing progressive embryologic stages in facial developmentusingscanningelectronmicroscopy(SEM)andto further understand upper-lip development. Design: The study was conducted at the California RegionalPrimateResearchCenter,Davis.Twentyprimateembryos (Macaca fascicularis) and 2 fetuses were examined with SEM. The development of the frontonasal prominence,maxillaryprominence,medialnasalprominence,and lateral nasal prominence were sequentially observed. The contribution of these prominences to the formation of the upper lip and nose were carefully analyzed. Results: The maxillary prominence and medial nasal prominence form the upper lip, whereas the lateral nasal, medial nasal, and maxillary prominences form the nose. There is fusion of the maxillary prominence with the medial nasal prominence. This fusion has not been previously described. This has resulted in a modification of the current theory of upper-lip development into one we refer to as the “dynamic fusion theory.” Conclusions: The dynamic fusion theory explains the merging process of the mesenchymal and ecotodermal layersofthefacialprominencesthatcontributetotheupper-lip formation. The dynamic fusion theory of facial prominence movement details the interaction between epithelial layers: both epithelial layers must fuse properly to avoid cleft-lip deformities.
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- 2003
5. Functional and Morphological Development of Lymphoid Tissues and Immune Regulatory and Effector Function in Rhesus Monkeys: Cytokine-Secreting Cells, Immunoglobulin-Secreting Cells, and CD5+B-1 Cells Appear Early in Fetal Development
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Tracy Rourke, Marta L. Marthas, Norbert Makori, Andrew G Hendrickx, Christopher J. Miller, Michael B. McChesney, Alice F. Tarantal, and Fabien X. Lü
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Microbiology (medical) ,Lymphocyte ,Clinical Biochemistry ,Immunology ,Antigen-Presenting Cells ,Immunoglobulins ,CD5 Antigens ,Immunophenotyping ,Embryonic and Fetal Development ,Interleukin 21 ,Fetus ,Immune system ,hemic and lymphatic diseases ,Cellular Immunology ,medicine ,Animals ,Immunology and Allergy ,Antigen-presenting cell ,CD40 ,biology ,Macrophages ,Dendritic Cells ,Immunohistochemistry ,Macaca mulatta ,Lymphocyte Subsets ,Intestines ,B-1 cell ,medicine.anatomical_structure ,Immune System ,biology.protein ,Cytokines ,Lymph Nodes ,Antibody ,CD5 ,Spleen - Abstract
Little is known regarding the timing of immune ontogeny and effector function in fetal humans and nonhuman primates. We studied the organization of lymphocyte and antigen-presenting cell populations in developing lymphoid tissues of rhesus monkey fetuses during the second and third trimesters (65 to 145 days of gestation; term = 165 days). Immunoglobulin-secreting and cytokine-secreting cells were detected at day 80. The thymus, spleen, lymph nodes, and intestinal mucosa were examined for cells expressing CD3, CD5, CD20, CD68, p55, and HLA-DR. In the spleens of 65-day-old fetuses (early second trimester), the overwhelming majority of total lymphocytes were CD5+CD20+B-1 cells. The remaining lymphocytes were CD3+T cells. By day 80, splenic B and T cells were equal in number. Intraepithelial CD3+CD5−T cells and lamina propria CD20+CD5+B cells were present in the intestines of 65-day-old fetuses. By day 80, numerous CD20+CD5+B cells were present in the jejunums and colons and early lymphocyte aggregate formation was evident. The spleens of 80- to 145-day-old fetuses contained immunoglobulin M (IgM)-secreting cells, while IgA-, IgG-, interleukin-6-, and gamma interferon-secreting cells were numerous in the spleens and colons. Thus, by the second trimester, the lymphoid tissues of the rhesus monkey fetus have a complete repertoire of properly organized antigen-presenting cells, T cells, and B cells.
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- 2003
6. Exposure of cynomolgus monkey embryos to retinoic acid causes thymic defects: effects on peripheral lymphoid organ development
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Pamela E. Peterson, Andrew G Hendrickx, Norbert Makori, and K. C. Lantz
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White pulp ,Pathology ,medicine.medical_specialty ,General Veterinary ,Lymphocyte ,Retinoic acid ,Spleen ,Aplasia ,Biology ,medicine.disease ,Hypoplasia ,chemistry.chemical_compound ,medicine.anatomical_structure ,Endocrinology ,Lymphatic system ,chemistry ,Internal medicine ,medicine ,Mesenteric lymph nodes ,Animal Science and Zoology - Abstract
We have previously reported that exposure of monkey embryos to 13-cis-retinoic acid (cRA) results in thymic defects. In this study, we analyzed lymphocyte and antigen-presenting cell populations at gestational days (GDs) 80-100 in the thymus, spleen, mesenteric lymph nodes, and gut-associated lymphoid tissue following a teratogenic dosing regimen of cRA (2.5 and 5 mg/kg) at GD14-27. Tissue sections were immunostained for T-cells (anti-CD3), B-cells (anti-CD20), dendritic cells (p55), and major histocompatibility class II (anti-HLA-DR). Digital images of spleen sections were analyzed to obtain the relative area occupied by the cell subsets within the white pulp (WP). Compared with controls, the T-cell dependent compartment of the spleen WP in specimens with perturbed thymic development (aplasia and severe hypoplasia) showed a reduction in size and proportion of CD3(+) T cells. Our findings indicate that cRA-induced thymic defects result in disrupted development of the splenic T-cell dependent compartment.
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- 2002
7. Two cases of digital defects inMacaca mulattainfants and a survey of the literature
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Pamela E. Peterson, Ross P. Tarara, Andrew G Hendrickx, and L. Brignolo
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Phalangeal duplication ,Ectrodactyly ,General Veterinary ,biology ,Polydactyly ,Anatomy ,Oligodactyly ,medicine.disease ,Nonhuman primate ,biology.animal ,Embryology ,medicine ,Animal Science and Zoology ,Primate ,Pathological - Abstract
Although congenital digital defects, particularly polydactyly, have been reported frequently in humans, their occurrence in rhesus macaques is relatively rare. We observed two cases of spontaneous digital defects in male rhesus monkey infants recently born at the California Regional Primate Research Center. One infant exhibited bilateral postaxial polydactyly and the other infant had bilateral oligodactyly with unilateral phalangeal duplication. In this report, we present the clinical/pathological details of these cases as well as discuss the embryology of normal and abnormal limb development. We will also summarize a variety of spontaneous and experimentally induced digital defects that have been reported in several nonhuman primate species.
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- 2002
8. Exposure to the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces squamous metaplasia in the endocervix of cynomolgus macaques
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Mary A. Scott, Ross P. Tarara, Bill L. Lasley, Kurt Benirschke, James W. Overstreet, and Andrew G Hendrickx
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Pathology ,medicine.medical_specialty ,Polychlorinated Dibenzodioxins ,Administration, Oral ,Uterine Cervical Neoplasms ,Cervix Uteri ,medicine.disease_cause ,Macaque ,biology.animal ,medicine ,Animals ,Cervix ,Metaplasia ,General Veterinary ,biology ,Transdifferentiation ,Cell Differentiation ,Epithelial Cells ,medicine.disease ,Squamous metaplasia ,Disease Models, Animal ,Macaca fascicularis ,stomatognathic diseases ,Cell Transformation, Neoplastic ,Teratogens ,medicine.anatomical_structure ,Carcinoma, Squamous Cell ,Epithelial Metaplasia ,Female ,Animal Science and Zoology ,Histopathology ,Carcinogenesis ,Endocervix - Abstract
Female cynomolgus macaques (n = 11) were treated orally with graded doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Cervical tissue was recovered at necropsy 1.2–2.7 years later and examined using routine histopathology. Results were compared histologically with cervical tissue from untreated, age- and parity-matched controls. Significant squamous epithelial metaplasia was observed in the endocervix of 9 of 11 TCDD-treated animals, and the degree of severity was dose dependent. In contrast, minimal or no pathological changes were observed in eight of nine control animals and one animal had only mild squamous metaplasia. These results suggest that TCDD exposure induces epithelial transdifferentiation in the primate cervix. Consequently, the TCDD-treated macaque may serve as a predictable animal model for the study of cervical epithelial transdifferentiation and for examining the relationship between squamous metaplasia and cervical oncogenesis both at the cellular and at the molecular level.
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- 2001
9. 13-cis-retinoic acid causes patterning defects in the early embryonic rostral hindbrain and abnormal development of the cerebellum in the macaque
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Norbert Makori, Pamela E. Peterson, and Andrew G Hendrickx
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Embryology ,Fetus ,Cerebellum ,Health, Toxicology and Mutagenesis ,Purkinje cell ,Hindbrain ,Embryo ,Anatomy ,Biology ,Toxicology ,Macaque ,Teratology ,medicine.anatomical_structure ,nervous system ,biology.animal ,embryonic structures ,medicine ,Cerebellar vermis ,Developmental Biology - Abstract
Background We have previously reported that exposure of embryos to 13-cis-retinoic acid (cRA) results in an abnormal phenotype of the fetal cerebellum. In this study, we analyzed early changes in the cerebellar anlagen (midbrain–hindbrain junction) as well as lesions of the fetal cerebellar vermis after a teratogenic dosing regimen of cRA in the macaque model. Methods We examined embryo coronal sections of the midbrain–hindbrain junction immunostained for Pax-2, Engrailed-2 (En-2) and Krox-20. To characterize the cerebellum foliation and fissure formation processes, we analyzed vermal cortical cell layer development and the number and depth of the major fissures on sagittal sections of fetal vermis. We also examined Purkinje cell development in vermal sections immunostained for CD3. Results Compared with controls, there was a consistent truncation of the midbrain–hindbrain region of early embryos exposed to cRA. The cRA-induced fetal vermis lesions included inhibition in its anteroposterior growth, altered folial patterning, a general loss of prominence of the fissures accompanied by a total loss of sublobular fissures, and changes in cortical cell layer development. CD3+ Purkinje cells were abnormally dispersed deep into the molecular layer in the vermis. Conclusions Our findings indicate that the effects of cRA on the developing cerebellum involve interference with the hierarchy of complex cellular and genetic interactions that lead to the growth and subdivision of the cerebellum into smaller units. The regional vermal defects may be related to early postnatal functional deficits. Teratology 63:65–76, 2001. © 2001 Wiley-Liss, Inc.
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- 2001
10. Humans and Old World monkeys have similar patterns of fetal globin expression
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Robert M. Johnson, Deborah L. Gumucio, Morris Goodman, Andrew G Hendrickx, Douglas A. Gage, Chi-hua Chiu, Steven Buck, and Tun Li Shen
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Fetus ,Old World ,Macaca nemestrina ,General Medicine ,Old World monkey ,Biology ,biology.organism_classification ,Molecular biology ,hemic and lymphatic diseases ,Gene expression ,Gene cluster ,Animal Science and Zoology ,Globin ,Gene - Abstract
The expression of epsilon- and gamma-globin mRNA and protein has been determined in three Old World monkey species (Macaca mulatta, Macaca nemestrina, and Cercopithecus aethiops). Using RT-PCR with primers for epsilon- and gamma-globin, both mRNAs were detected in early fetal stages, whereas at 128 days (85% of full term), only gamma was expressed. High-performance liquid chromatography was used for separation and quantitation, and matrix-assisted laser desorption/ionization mass spectrometry was used for identification of globin polypeptides. An alpha-globin polymorphism was observed in all of the species examined. During fetal life, gamma-globin was the predominant expressed beta-type globin. The red blood cells of infants still contained substantial amounts of gamma-globin, which declined to negligible levels in 14 weeks as beta-globin expression reached adult values. The ratio of gamma1- to gamma2-globins (equivalent to Ggamma/Agamma in humans) was approximately 2.5, similar to the Ggamma/Agamma ratio observed in humans. Thus, gamma-globin gene expression in these Old World monkeys species has three features in common with human expression: expression of both duplicated gamma genes, the relative preponderance of gamma1 over gamma2 expression, and the delay of the switch from gamma- to beta-globin until the perinatal period. Thus, the catarrhines seem to share a common pattern of developmental switching in the beta-globin gene cluster, which is distinct from the timing of expression in either prosimians or the New World monkeys. Our results indicate that an Old World monkey, such as Rhesus, could serve as a model organism (resembling humans) for experimentally investigating globin gene expression patterns during the embryonic, fetal, and postnatal stages.
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- 2000
11. Conjoined twins in a rhesus monkey (Macaca mulatta)
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Andrew G Hendrickx, L. Brignolo, Don R. Canfield, and Pamela E. Peterson
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Male ,Cord ,General Veterinary ,biology ,Amnion ,Umbilicus (mollusc) ,Anatomy ,medicine.disease ,Macaca mulatta ,body regions ,medicine.anatomical_structure ,Liver Lobe ,Pregnancy ,biology.animal ,Placenta ,Conjoined twins ,medicine ,Animals ,Female ,Animal Science and Zoology ,Primate ,Twins, Conjoined ,Umbilical region - Abstract
Conjoined twinning is an extremely rare occurrence among human and nonhuman primates. The current report describes a case of minimally conjoined omphalopagus rhesus monkey twins that were observed in the breeding colony at the California Regional Primate Research Center. The full-term nonviable male twins were morphologically normal and united in the umbilical region, involving the liver, xiphoid, umbilicus, body wall, and skin. The umbilical cords were separate, but closely aligned, within an ensheathing amnion; each cord contained two arteries and a vein. The closely associated cords were centrally inserted on a large bidiscoid placenta. There were no gross or histologic abnormalities in the viscera, with the exception of enlargement of the left central liver lobes, which constituted the area of attachment. The cause of death was attributed to asphyxia and trauma experienced during parturition.
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- 2000
12. Vitamin A teratogenicity and risk assessment in the macaque retinoid model
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Hans Hummler, Andrew G Hendrickx, Pamela E. Peterson, and D. Hartmann
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Vitamin ,medicine.medical_specialty ,No-observed-adverse-effect level ,Retinoid embryopathy ,Administration, Oral ,Biology ,Toxicology ,Risk Assessment ,chemistry.chemical_compound ,Pregnancy ,Oral administration ,Internal medicine ,medicine ,Animals ,Humans ,Isotretinoin ,Vitamin A ,Chromatography, High Pressure Liquid ,No-Observed-Adverse-Effect Level ,Dose-Response Relationship, Drug ,Retinol ,Abnormalities, Drug-Induced ,medicine.disease ,Teratology ,Disease Models, Animal ,Macaca fascicularis ,Teratogens ,Endocrinology ,chemistry ,Area Under Curve ,Gestation ,Female - Abstract
Studies were performed in the cynomolgus monkey (Macaca fascicularis) to provide risk assessment information on safe dose levels of Vitamin A during human pregnancy. Vitamin A palmitate was orally administered at 7500 IU/kg (2.25 mg/kg) to 80 000 IU/kg (24 mg/kg) body weight during early pregnancy (gestation day [GD] 16-27). The results indicated a dose-related increase in exposure (AUC) to retinyl esters and retinoic acids (RA) (all-trans-RA, all-trans-4-oxo-RA, 13-cis-RA, 13-cis-4-oxo-RA). There was also a dose-related increase in abortion and malformation that affected typical retinoid target tissues in the embryo, including the craniofacial region, heart, and thymus. The NOAEL and LOAEL for structural malformations were 7500 IU/kg and 20 000 IU/kg (6 mg/kg), respectively. A companion study involving oral administration of 13-cis-RA during the same gestational period established the NOAEL for malformations at 0.5 mg/kg/day, which is close to the human therapeutic dose range (0.5 to 1.5 mg/kg/day) associated with retinoid embryopathy. Based on the known similarities in teratogenic susceptibility to 13-cis-RA, the monkey NOAEL for Vitamin A (7500 IU/kg) was used to estimate safe levels of this nutrient in humans applying a safety factor of 10. This approach yielded safe levels of Vitamin A during human pregnancy in the range of approximately 25 000 to 37 000 IU/day.
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- 2000
13. A history of the Teratology Society
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Mason Barr, Andrew G Hendrickx, William J. Scott, Thomas H. Shepard, Robert L. Brent, Godfrey P. Oakley, and D. M. Kochhar
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Gerontology ,Embryology ,Medical education ,business.industry ,Health, Toxicology and Mutagenesis ,media_common.quotation_subject ,Toxicology ,Teratology ,Politics ,Medicine ,Social content ,business ,Health policy ,Developmental Biology ,Diversity (politics) ,media_common - Abstract
Background: The 39-year history of the Teratology Society is reviewed. An abbreviated history is outlined in table form, along with listings of the Warkany Lectures, the postgraduate courses, and officers of the Society. Methods: A year-by-year description of the events, including the scientific and social content of the annual meetings and changes in the business of the Society, is given, in many cases using comments from the past presidents. The valuable and unique diversity of the members is discussed and illustrated, presenting the disciplines and main research area of the presidents. The number of submitted abstracts and the various categories are tabulated, averaging the number and type over four periods. Within the past 10 years, a significant increase in the number of abstracts dealing with epidemiology and developmental biology is evident. The Society’s development is compared with that of a human, and the question is asked: Have we reached the maturational stage of old age or senescence, or is the Society still maturing gracefully? This question needs further discussion by all the members. Results: During the past 40 years, we have developed the scientific basis to prevent birth defects caused by rubella, alcoholism, and folate deficiency, as well as many other prenatal exposures. Conclusions: We must now engage in the political battles to obtain the resources needed to conduct further research and to implement the prevention programs, as well as to provide care and rehabilitation for persons with birth defects.
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- 2000
14. Pathogenesis of retinoic acid-induced ear malformations in a primate model
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Norbert Makori, Andrew G Hendrickx, Xin Wei, Pamela E. Peterson, and Hans Hummler
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Auricle ,Second pharyngeal arch ,Embryology ,First pharyngeal arch ,Health, Toxicology and Mutagenesis ,Incus ,Retinoic acid ,Malleus ,Anatomy ,Biology ,Toxicology ,medicine.disease ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Anotia ,medicine ,Middle ear ,Developmental Biology - Abstract
13-cis retinoic acid (RA) is a causative agent for human/monkey retinoic acid embryopathy (RAE), in which the most common type of malformation is microtia or anotia. In the present study, malformed ears of monkey fetuses exposed to RA during early embryogenesis were analyzed and revealed a subtype of defects., i.e., apparent duplication of the external/middle ear. A part of the posterior auricle appeared to be ectopically formed in the anterior auricular region or in the region posterior to the auricle. Additionally, there was duplication of the zygomatic arch, malleus, and incus. In order to characterize possible pathogenetic events underlying these malformations, embryos at selected stages were collected after dosing dams with RA at 5 mg/kg/day during gestational days 12-27. Cellular retinoic acid binding protein I whole-mount immunostaining showed that RA induced specific alterations in the migration of cranial neural crest cells (NCC). NCC en route to the second pharyngeal arch were bifurcated, and some of these NCC migrated abnormally into the first and/or third arches, which may underlie external ear duplication. Scanning electron microscopy and neurofilament immunostaining provided evidence that there was partial duplication of trigeminal nerve/ganglion following RA insult. The duplication of NCC neuronal derivatives in the first pharyngeal arch is consistent with duplication of NCC mesenchymal components (zygomatic arch, malleus, and incus). Therefore, RA-induced alterations in cranial NCC migration patterns are likely to be a pathogenetic event underlying ear malformations (including duplication) of RAE in monkeys.
- Published
- 1999
15. Endocrine Biomarkers of Early Fetal Loss in Cynomolgus Macaques (Macaca fascicularis) Following Exposure to Dioxin1
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Lisa S. Laughlin, Alice F. Tarantal, Dennis R. Stewart, Yumei Guo, Jacquelyn A. Dieter, Bill L. Lasley, James W. Overstreet, and Andrew G Hendrickx
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Relaxin ,endocrine system ,medicine.medical_specialty ,medicine.drug_class ,media_common.quotation_subject ,Estrone ,Cell Biology ,General Medicine ,Biology ,chemistry.chemical_compound ,Endocrinology ,Reproductive Medicine ,chemistry ,Estrogen ,Internal medicine ,medicine ,Endocrine system ,Gonadotropin ,Reproductive toxicity ,Ovulation ,reproductive and urinary physiology ,media_common ,Hormone - Abstract
This study examines the endocrine alterations associated with early fetal loss (EFL) induced by an environmental toxin, TCDD (2,3,7, 8-tetrachlorodibenzo-p-dioxin), in the cynomolgus macaque, a well-documented reproductive/developmental model for humans. Females were administered single doses of 1, 2, and 4 microgram/kg TCDD (n = 4 per dose group) on gestational day (GD) 12. Urinary estrogen metabolites (estrone conjugates) were monitored to establish the day of ovulation, and serum hormones (estradiol, progesterone, chorionic gonadotropin, relaxin) were measured to assess ovarian and placental endocrine status before and after treatment. EFL occurred between GDs 22 and 32 in 10 of the 12 animals treated with TCDD. The primary endocrine alterations associated with TCDD treatment were significant decreases in serum estradiol and bioactive chorionic gonadotropin concentrations (p < 0.02). Less pronounced decreases in serum progesterone (p = 0.10) and relaxin (p < 0.08) also followed TCDD treatment. In contrast, immunoreactive chorionic gonadotropin concentrations were not reduced by TCDD exposure at any level, indicating that TCDD targets specific components of the chorionic gonadotropin synthesis machinery within the trophoblast to alter the functional capacity of the hormone. These data demonstrate the value of endocrine biomarkers in identifying a toxic exposure to primate pregnancy many days before direct signs of reproductive toxicity were apparent. The increased EFL that occurred after exposure to TCDD might reflect a toxic response initially mediated via endocrine imbalance, leading to placental insufficiency, compromised embryonic circulation, and subsequent EFL.
- Published
- 1999
16. Retinoid teratogenicity in the macaque: Verification of dosing regimen
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Hans Hummler, Georg Tzimas, R. Korte, and Andrew G Hendrickx
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medicine.drug_class ,Retinoid embryopathy ,Retinoic acid ,Pharmacology ,Macaque ,Drug Administration Schedule ,Retinoids ,chemistry.chemical_compound ,Fetus ,Pharmacokinetics ,Pregnancy ,biology.animal ,medicine ,Animals ,Retinoid ,Adverse effect ,General Veterinary ,biology ,Abnormalities, Drug-Induced ,Lowest-observed-adverse-effect level ,Macaca fascicularis ,chemistry ,Pregnancy, Animal ,Gestation ,Female ,Animal Science and Zoology - Abstract
To further define teratogenicity associated with 13-cis-retinoic acid (13-cis-RA) in the cynomolgus monkey, the drug was orally administered on three different treatment regimens. Experiment (Exp.) 1 (2.5 mg/kg/day, gestational day [GD] 12–27, n = 11) investigated the teratogenicity of a single daily dose of 13-cis-RA administered shortly after embryo implantation. Pharmacokinetic sampling was done to determine retinoid profiles on the first (GD12) and last (GD27) days of treatment. Exposure to 13-cis-RA during early organogenesis in Exp. 2 (2.5 mg/kg/day, GD20–27, and 2 × 2.5 mg/kg/day, GD28–30, n = 5) investigated the potential adverse effects of 13-cis-RA on the developing limb. The use of multiple doses of 13-cis-RA in Exp. 3 (2 × 2.5 mg/kg/day, GD26–27, n = 5) investigated the necessity of double dosing on the induction of retinoid embryopathy in the macaque. Malformations of retinoid target organs as well as embryolethality were most prevalent when single daily doses of 13-cis-RA were administered during pre- and early organogenesis in Exp. 1. Moreover, multiple doses on GD26–27 failed to induce any manifestation of abnormal development in Exp. 3. These results confirm that the lowest observed adverse effect level (LOAEL) in macaques is 2.5 rather than 5.0 times greater than that observed in human pregnancies. Exposure during forelimb development (GD20–30) in Exp. 2 was unsuccessful in inducing defects of this skeletal region, although defects in several retinoid target organs (i.e., cerebellum and internal ear) were present, indicating that a teratogenic threshold was achieved. Pharmacokinetic analysis of 13-cis-RA and its metabolites on GD12 and 27 in Exp. 1 showed considerable exposure to the administered drug and its 4-oxo-metabolite. In contrast, the exposure to all-trans-RA was negligible. The results support the use of a specific treatment schedule in early gestation in the macaque as the most appropriate model for characterizing the teratogenic potential of retinoids in humans.
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- 1998
17. Effects of 13-cis-retinoic acid on hindbrain and craniofacial morphogenesis in long-tailed macaques (Macaca fascicularis)
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Pamela E. Peterson, Andrew G Hendrickx, Thomas N. Blankenship, Hans Hummler, Norbert Makori, and Lisa Dillard-Telm
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animal structures ,Retinoic acid ,Rhombomere ,Organogenesis ,Hindbrain ,Biology ,Craniofacial Abnormalities ,Embryonic and Fetal Development ,chemistry.chemical_compound ,Cranial neural crest ,Cell Movement ,Animals ,Craniofacial ,Isotretinoin ,Face and neck development of the embryo ,General Veterinary ,Genes, Homeobox ,Neural crest ,Anatomy ,Rhombencephalon ,Macaca fascicularis ,Teratogens ,chemistry ,Neural Crest ,embryonic structures ,Pharynx ,Female ,Animal Science and Zoology - Abstract
Hindbrain and craniofacial development during early organogenesis was studied in normal and retinoic acid-exposed Macaca fascicularis embryos. 13-cis-retinoic acid impaired hindbrain segmentation as evidenced by compression of rhombomeres 1 to 5. Immunolocalization with the Hoxb-1 gene product along with quantitative measurements demonstrated that rhombomere 4 was particularly vulnerable to size reduction. Accompanying malformations of cranial neural crest cell migration patterns involved reduction and/or delay in pre- and post-otic placode crest cell populations that contribute to the pharyngeal arches and provide the developmental framework for the craniofacial region. The first and second pharyngeal arches were partially fused and the second arch was markedly reduced in size. The otocyst was delayed in development and shifted rostrolaterally relative to the hindbrain. These combined changes in the hindbrain, neural crest, and pharyngeal arches contribute to the craniofacial malformations observed in the retinoic acid malformation syndrome manifested in the macaque fetus.
- Published
- 1998
18. Neuropathogenesis Induced by Rhesus Cytomegalovirus in Fetal Rhesus Monkeys (Macaca mulatta)
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Andrew G Hendrickx, M. Shahriar Salamat, Peter A. Barry, William J. Britt, Paul A. Luciw, and Alice F. Tarantal
- Subjects
Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Congenital cytomegalovirus infection ,Intrauterine growth restriction ,Lissencephaly ,Gestational Age ,Macaque ,Pregnancy ,biology.animal ,medicine ,Polymicrogyria ,Animals ,Immunology and Allergy ,Meningitis ,Primate ,Gliosis ,Hysterotomy ,Brain Diseases ,biology ,Brain ,Calcinosis ,medicine.disease ,Macaca mulatta ,Disease Models, Animal ,Fetal Diseases ,Infectious Diseases ,Cytomegalovirus Infections ,Female ,Ventriculomegaly - Abstract
Rhesus cytomegalovirus (RhCMV) infection of rhesus macaques offers opportunities to analyze mechanisms of CMV pathogenesis in a primate species. Four fetal rhesus monkeys were inoculated intraperitoneally with RhCMV early in the second trimester, and pregnancies were terminated by hysterotomy during the third trimester. Three fetuses had evidence of severe CMV disease, including intrauterine growth restriction, ventriculomegaly, microcephaly, lissencephaly, and extensive degenerative changes of the cerebral parenchyma. Histopathologic examination revealed polymicrogyria, gliosis, leptomeningitis, periventricular calcifications, and inclusion-bearing cells. These results demonstrate that the developing macaque brain is susceptible to infection with RhCMV early in the second trimester and that intrauterine infection results in neuropathologic outcomes similar to those observed in humans congenitally infected with CMV.
- Published
- 1998
19. Symposium: reproduction in baboons. From blastocyst to placenta: the morphology of implantation in the baboon
- Author
-
Allen C. Enders, Pamela E. Peterson, Andrew G Hendrickx, and K. C. Lantz
- Subjects
Cytotrophoblast ,Uterus ,Obstetrics and Gynecology ,Trophoblast ,Placentation ,Anatomy ,Biology ,Endometrium ,Andrology ,medicine.anatomical_structure ,Reproductive Medicine ,Placenta ,embryonic structures ,medicine ,Inner cell mass ,Blastocyst ,reproductive and urinary physiology - Abstract
Implantation and placentation in the baboon share many morphological features with other primates, as well as having some specific distinctions. The ability to use deturgescence of the sex skin as a method of timing ovulation and the ease with which the uterine lumen can be flushed have been used to examine morphological aspects of blastocyst differentiation and implantation in this species. Preimplantation blastocysts were obtained by non-surgical flushing of the uterus 6-8 days after ovulation, and implantation sites were excised from uteri removed on days 10-16 of gestation. All tissues were prepared for electron microscopy by aldehyde fixation and plastic embedding. Maturation of trophoblast from the compacted morula stage to the expanded blastocyst stage includes increase in numbers of polyribosomes, changes in conformation of mitochondria, and development of an effective endocytic apparatus. An endodermal layer forms beneath the inner cell mass prior to loss of the zona pellucida, and parietal endodermal cells extend beyond the inner cell mass. Azonal blastocysts have regions of syncytial trophoblast adjacent to the inner cell mass, and they may represent adhesion stages of early implantation. In early postimplantation stages, trophoblast replaces the uterine epithelium and processes of syncytial trophoblast invade dilated superficial maternal vessels. In subsequent lacunar stages there is rapid elevation of the developing conceptus above the uterine surface as the lacunae enlarge. Cytotrophoblast rapidly enters maternal vessels, and arterioles are partially or completely occluded by migrating cytotrophoblast. The early access to controlled maternal blood flow apparently allows trophoblastic lacunae to expand superficially as opposed to more extensive endometrial invasion.
- Published
- 1997
20. Symposium: reproduction in baboons. Perspectives on the use of the baboon in embryology and teratology research
- Author
-
Pamela E. Peterson and Andrew G Hendrickx
- Subjects
Pregnancy ,Triamcinolone acetonide ,biology ,Obstetrics and Gynecology ,Physiology ,medicine.disease ,Macaque ,Teratology ,medicine.anatomical_structure ,Reproductive Medicine ,biology.animal ,Embryology ,Immunology ,medicine ,Pyridoxine/doxylamine ,Nose ,medicine.drug ,Baboon - Abstract
This paper summarizes the developmental stages of the baboon during the period of organ formation and provides comparative information for other primates, including the human. Special attention is directed to the early development of the nervous system, eye, ear and nose/palate. The similarity in development of these structures with humans indicates that the baboon is a suitable model for studies of normal and abnormal neurological development. Spontaneous prenatal loss rates in the baboon (2.4-11.2%) are slightly lower than those reported in rhesus and cynomologus monkeys. The baboon, in addition to the cynomologus monkey and macaque, has been used as a model in teratology research to assess the potential risk of thalidomide, sex steroids, Bendectin and rubella virus, as well as to study the pathogenesis of malformations associated with the corticosteroid triamcinolone acetonide. The rate of spontaneous malformations (
- Published
- 1997
21. Morphology of a six-legged goat with duplication of the intestinal, lower urinary, and genital tracts
- Author
-
D. Oduor-Okelo, G. E. Otiang'a-Owiti, Norbert Makori, Andrew G Hendrickx, and George K. Kamau
- Subjects
Pathology ,medicine.medical_specialty ,Urinary bladder ,Urinary system ,Anatomy ,Biology ,Intestinal Duplication ,Agricultural and Biological Sciences (miscellaneous) ,medicine.anatomical_structure ,Urethra ,Gene duplication ,medicine ,Capra hircus ,Bladder duplication ,Sex organ - Abstract
Background: An adult female goat with rare malforma- tions, which consisted of duplication of the intestinal, lower urinary, and genital tracts as well a pair of parasitic appendages, is presented. Methods: A complete dissection was performed on a moribund female goat (Capra hircus). Results: The animal had a normal body with a parasitic attachment located within the pelvic region. This attachment was represented by an ovoid, trunk-like, adipose mass that lacked internal organs or vertebrae but that had two fairly well-developed limbs with the normal components of hind limbs. There was duplication involving the external and internal genitalia, the urethra, the urinary bladder, and portions of the small intestine as well as the large bowel, including the anal openings. Conclusions: An autosite with a duplication involving the hindgut and paramesonephric anlages was identified. These features were compatible with life in utero and postutero and emanated from incomplete twinning (heteropagus twins).Areview of the literature also suggests that heteropa- gus twins are a very rare abnormality in both domestic animals and humans. Anat. Rec. 247:432-438, 1997 r 1997 Wiley-Liss, Inc.
- Published
- 1997
22. Effects of finasteride, a type 2 5-alpha reductase inhibitor, on fetal development in the rhesus monkey (Macaca mulatta)
- Author
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K. I. Mackenzie, L. F. Kruk, M. A. Cukierski, Alice F. Tarantal, G. L. Skiles, A. P. Clarke, G. S. Harris, K. P. Ellsworth, C. P. Peter, Andrew G Hendrickx, D. S. Ablin, M. J. Vanzwieten, and S. Prahalada
- Subjects
Embryology ,medicine.medical_specialty ,Fetus ,Health, Toxicology and Mutagenesis ,Alpha (ethology) ,Biology ,Toxicology ,Teratology ,chemistry.chemical_compound ,5 Alpha-Reductase Inhibitor ,Endocrinology ,chemistry ,In utero ,Dihydrotestosterone ,Internal medicine ,medicine ,Finasteride ,Testosterone ,Developmental Biology ,medicine.drug - Abstract
In genetic male fetuses, dihydrotestosterone (DHT) plays an important role in normal prostatic and external genital differentiation. The enzyme steroid 5-alpha reductase (5 alpha R) catalyzes the conversion of testosterone (T) to DHT. The importance of 5 alpha R in sexual differentiation is evident from the study of human genetic males who congenitally lack this enzyme and consequently develop ambiguous genitalia. These individuals are specifically deficient in the type 2 isozyme, whereas the normal type 1 isozyme activity has been found. The purpose of this study was to determine 1) the suitability of the rhesus monkey for testing the safety of 5 alpha R inhibitors when administered during pregnancy and 2) the potential risk of administering a known type 2 5 alpha R inhibitor, finasteride, during the critical period of internal and external genital differentiation in rhesus monkeys. In vitro studies were also performed on selected rhesus monkey tissues to determine the distribution of the 5 alpha R isozymes. Gravid monkeys were treated once daily from gestational days (GD) 20 to 100. Sonographic monitoring was performed during the course of gestation to monitor viability, growth, and organ system development. Detailed fetal evaluations for developmental abnormalities were performed at term (GD 152 +/- 2). A group of 13 pregnant monkeys ("positive control") were given a high oral dose (2 mg/kg/day) of finasteride to demonstrate that inhibiting type 2 5 alpha R results in specific external genital abnormalities in male fetuses. Thirty-two pregnant monkeys were administered an intravenous (i.v.) formulation of finasteride at doses of 8, 80, or 800 ng/day. The highest i.v. dose selected was at least 60-750 times the semen levels of finasteride in man given orally 5 or 1 mg/day, respectively. Seventeen vehicle-control pregnant monkeys were also included. Administration of a high oral dose (2 mg/kg/day) of finasteride resulted in external genital abnormalities characterized by hypospadias, preputial adhesions to the glans, a small underdeveloped scrotum, a small penis, and a prominent midline raphe in male fetuses; however, no developmental abnormalities were seen in female fetuses. Similarly, no abnormalities were observed in either male or female fetuses of mothers given iv doses (8, 80, or 800 ng/day) of finasteride during pregnancy. The in utero sonographic findings in fetuses correlated with the gross findings at term. These studies have shown that external genital abnormalities can be produced in male monkey fetuses when exposed to a high oral dose (2 mg/kg/day) of finasteride, whereas no abnormalities were observed in fetuses exposed to the i.v. formulation of finasteride. Detailed in vitro studies demonstrated that the rhesus monkey also has two 5 alpha R isozymes (types 1 and 2) with a tissue distribution similar to that seen in man and, furthermore, that finasteride is a potent, mechanism-based inhibitor with selectivity for both human and rhesus type 2 5 alpha R. These studies have demonstrated that the monkey is a suitable model for assessing the safety of 5 alpha R inhibitors administered during pregnancy.
- Published
- 1997
23. ELISA for the measurement of serum and urinary chorionic gonadotropin concentrations in the laboratory macaque
- Author
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Andrew G Hendrickx, C. J. Munro, Lisa S. Laughlin, J. C. Illera, Bill L. Lasley, and Jacquelyn A. Dieter
- Subjects
Antiserum ,endocrine system ,medicine.medical_specialty ,medicine.drug_class ,Radioimmunoassay ,Urine ,Biology ,Human chorionic gonadotropin ,Endocrinology ,Polyclonal antibodies ,Internal medicine ,medicine ,biology.protein ,Animal Science and Zoology ,Gonadotropin ,Antibody ,Luteinizing hormone ,Ecology, Evolution, Behavior and Systematics - Abstract
A rapid, sensitive, enzyme-linked immunosorbant assay (ELISA) for the measurement of chorionic gonadotropin (CG) in serum and urine samples of laboratory macaques is reported. The ligand (CG) is captured by a readily available, widely used, and well-characterized monoclonal antibody (Mab, 518B7) generated against the beta subunit of bovine luteinizing hormone (LH). This Mab, while specific for LH, shows very little species specificity, and has been shown to detect LH and CG by radioimmunoassay (RIA) in both human and non-human primates. A polyclonal antiserum raised in rabbits against human chorionic gonadotropin (hCG) is conjugated to horseradish peroxidase, and is used as the second antibody signal. This anti-hCG antiserum cross reacts with CG secreted by both the human (hCG) and macaque (mCG). The ELISA utilizes hCG as the standard, and results are based on the relative concentrations of mCG in serum and urine. Total assay time is less than 5 hours. Range of the standard curve is 0.002 to 0.5 ng hCG/well, and the least detectable concentration of hCG is 0.0023 +/- 0.0007 ng/well. Pregnancy was detected in early pregnant macaques (M. fascicularis) on 9 (N = 1/16), 10 (N = 1/16), 11 (N = 1/16), 12 (N = 6/16), 13 (N = 1/16), 14 (N = 4/16), and 15 (N = 2/16) days following the pre-ovulatory urinary estrone conjugate peak. The detection of pregnancy by urinary mCG occurred approximately 24 to 72 hours after its detection in serum.
- Published
- 1997
24. Activity and attention in zinc-deprived adolescent monkeys
- Author
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M E Gershwin, Man S. Golub, Carl L. Keen, P T Takeuchi, and Andrew G Hendrickx
- Subjects
Aging ,medicine.medical_specialty ,Rest ,media_common.quotation_subject ,Medicine (miscellaneous) ,chemistry.chemical_element ,Zinc ,Lethargy ,Cognition ,Bone Density ,Internal medicine ,medicine ,Animals ,Sexual Maturation ,Effects of sleep deprivation on cognitive performance ,Growth Disorders ,media_common ,Nutrition and Dietetics ,Behavior, Animal ,Water Deprivation ,Growth retardation ,business.industry ,Monkey Diseases ,Haplorhini ,Late adolescence ,Micronutrient ,medicine.disease ,Circadian Rhythm ,Malnutrition ,Endocrinology ,chemistry ,Female ,Energy Metabolism ,Food Deprivation ,business ,Vigilance (psychology) - Abstract
Lethargy is characteristic of malnourished pop- ulations, but little is known about the biologic mechanism or consequences for cognitive performance. In the current experi- ment, 24-h activity patterns and performance of an attention task were studied in adolescent female monkeys ( 18-33 mo of age, n = 10/group) under conditions of moderate dietary zinc depriva- tion (2 � Zn/g diet) and adequate dietary zinc (50 �g Zn/g). There were progressive decreases in daytime activity levels in the zinc- deprived group followed by slowing of growth around the time of the growth spurt. Attention performance was also impaired before the onset of growth retardation. Zinc-deprived monkeys failed to show the shift to later initiation of the rest phase of the diurnal cycle seen in controls in late adolescence. These data support previous findings that activity and attention can be affected during early stages of zinc deprivation before the onset of growth retar- dation. Am J Clin Nutr 1996;64:908-l5.
- Published
- 1996
25. Retinoid metabolism and transplacental pharmacokinetics in the cynomolgus monkey following a nonteratogenic dosing regimen with all-trans-retinoic acid
- Author
-
Georg Tzimas, Hans Hummler, Pamela E. Peterson, Andrew G Hendrickx, and Heinz Nau
- Subjects
Embryology ,medicine.medical_specialty ,Fetus ,Chemistry ,medicine.drug_class ,Health, Toxicology and Mutagenesis ,Transplacental ,Pharmacology ,Toxicology ,Teratology ,Endocrinology ,Pharmacokinetics ,Oral administration ,Internal medicine ,Toxicity ,medicine ,Retinoid ,Dosing ,Developmental Biology - Abstract
Retinoids often exhibit a complex metabolic pattern and differential transplacental kinetics, which make it difficult to pinpoint the proximate compound responsible for the observed teratogenic effect. We have therefore studied the pharmacokinetics and metabolism of all-trans-retinoic acid (all-trans-RA) in cynomolgus monkeys following application of a nonteratogenic dosing regimen and compared the results with corresponding data from a previous study with a teratogenic dosing regimen with 13-cis-RA [Hummler et al. (1994) Teratology 50:184-193]. All-trans-RA was administered to pregnant cynomolgus monkeys (Macaca fascicularis) by nasogastric intubation at a dose of 5 mg/kg body wt once daily from gestational day (GD) 16 to 26 and twice daily at 8-h intervals from GD 27 to 31. Examination of the fetuses of four dams on GD 100 +/- 2 showed no embryotoxic or teratogenic effects of the applied dosing regimen (Experiment 1). Maternal plasma retinoid pharmacokinetics on GD 16, 26, and 31 as well as embryonic retinoid profiles after the last drug administration on GD 31 were determined in thirteen further dams (Experiment 2). All-trans-RA reached much lower plasma concentrations after the last two treatments on GD 31 than after the first one on GD 16 and the eleventh one on GD 26 (0-24-h area-under-the-concentration-time-curve (AUC) values: 104 +/- 59 ng x h/ml (after the last treatment on GD 31), 189 +/- 110 (GD 16) and 393 +/- 305 ng x h/ml (GD 26). The predominant plasma metabolites of all-trans-RA were its beta-glucuronide and the beta-glucuronide of all-trans-4-oxo-RA. Both of these retinoids accumulated in the plasma during the period of treatment and displayed AUC values 5- to 30-fold higher than those of all-trans-RA. Embryonic concentrations of all-trans-RA were not increased over endogenous levels after the last administration on GD 31 when plasma concentrations were low. To evaluate the placental transport of all-trans-RA in the presence of high plasma concentrations, a further experiment was performed, in which a single dose of all-trans-RA (10 mg/kg body wt) was given to four pregnant monkeys on GD 31, and plasma pharmacokinetics as well as embryonic concentrations of retinoids at 4 h post-treatment were determined (Experiment 3). This dosing schedule yielded high plasma concentrations of all-trans-RA, while embryonic concentrations were about 40% of plasma levels. Based on the plasma AUC values on GDs 16 and 26 obtained in Experiment 2 and the degree of placental transfer, as determined on GD 31 in the presence of high plasma levels in Experiment 3, we estimated embryonic AUC values for the 24-h period following the nonteratogenic doses on GDs 16 and 26 in Experiment 2. These AUC values were similarly high to the embryonic AUC value of all-trans-RA obtained after application of the teratogenic dosing regimen with 13-cis-RA [Hummler et al. (1994) Teratology 50:184-193]. In addition, plasma AUC values of all-trans-RA were 2- to 7-fold higher after all-trans-RA administration (present study) than after dosing with the teratogenic dose of 13-cis-RA. These results strengthen our recent suggestion that the teratogenic effects induced in cynomolgus monkeys by 13-cis-RA treatment cannot solely result from the action of all-trans-RA, but may involve 13-cis-RA and 13-cis-4-oxo-RA, which could act directly or function as transport vehicle.
- Published
- 1996
26. Development of the brain in staged embryos of the long-tailed monkey (Macaca fascicularis)
- Author
-
Cruz G. Rodriguez, Norbert Makori, Andrew G Hendrickx, and M. A. Cukierski
- Subjects
Trigeminal nerve ,biology ,Animal ecology ,biology.animal ,Animal Science and Zoology ,Primate ,Primordium ,Embryo ,Anatomy ,Hippocampal formation ,Macaque ,Baboon - Abstract
The external characteristics and successive morphological changes of the brain and its derivatives were studied in 69 long-tailed monkey embryos representing developmental stages 8 through 16. This morphogenesis follows a similar pattern to those of the rhesus, baboon, and human. Minor differences in the temporal sequence of specific developmental events include: 1) otic disc, adenohypophyseal pouch, and hippocampal internal sulcus formation in the long-tailed macaque occur at stage 10, stage 11, and after stage 16 respectively, which is comparable to human stages 9, 10, and 16; 2) formation of the trigeminal primordium and the motor root of the trigeminal nerve and evagination of the neurohypophysis occur at stage 12, stage 14, and stage 15, while in the human embryo these features are observed at stage 14, stage 15, and stage 16, respectively; and 3) closure of the lens pore, like in the rhesus monkey, occurs during stage 15, while in the baboon and human it takes place during stage 14. These temporal differences in the embryonic period are important factors to be taken into consideration in any embryological and teratological studies when usingM. fascicularis as a primate model.
- Published
- 1996
27. Implantation and early pregnancy: Effect of single-dose, early luteal phase administration of mifepristone (RU486) on implantation stage endometrium in the rhesus monkey
- Author
-
Andrew G Hendrickx, Jayasree Sengupta, and Debabrata Ghosh
- Subjects
medicine.medical_specialty ,media_common.quotation_subject ,Rehabilitation ,Uterus ,Obstetrics and Gynecology ,Mifepristone ,Luteal phase ,Biology ,Endometrium ,Glandular Differentiation ,Endocrinology ,medicine.anatomical_structure ,Reproductive Medicine ,In utero ,Internal medicine ,medicine ,Alkaline phosphatase ,Ovulation ,medicine.drug ,media_common - Abstract
The characteristics of implantation stage endometrium following a single-dose, early luteal phase application of mifepristone (RU486) in proven conception cycles has been examined in the rhesus monkey in an attempt to understand the physiological basis of the anti-implantation activity of the drug. Endometrial samples were collected from monkeys subjected to vehicle (group 1, n = 14) and RU486 (2 mg/kg body weight; group 2, n = 12) on day 2 after the presumed day of ovulation of successfully mated cycles. The average diameter of glands (P < 0.05), number of vacuolated cells (P < 0.01), number of supranuclear vacuolated cells (P < 0.05) in glandular epithelium and amount of glandular secretion (P < 0.05) were significantly lower in RU486-treated endometrium compared with control tissue samples. Additionally, 18% of glandular epithelial cells showed apoptotic and degenerative features in RU486-treated tissue samples. These data, together with the observed significant decreases in precipitate area (P < 0.02) and in the optical absorbance of alkaline phosphatase reaction end-product (P < 0.05), confirm that retardation in glandular differentiation in the upper functionalis is a likely target of antiprogestin action in implantation stage endometrium. An increased frequency of mitosis in stromal cells (P < 0.05) and a greater degree of extravasation (P < 0.05) were also observed after RU486 exposure. Despite an apparent indication of constriction and regression in few RU486-exposed endometria compared with controls, morphometric analyses did not show any changes in capillary structure. Whether endometrial vasculature in progesterone-exposed uterus is a target of antiprogestin action during the peri-implantation stage remains to be determined. Further studies are required to explain the observed increase (P < 0.02) in the area of precipitate of von Willebrand (vW) factor with no change in vW factor-positive vessels, and the apparent increase in collagen IV immunostain in subepithelial and perivascular basement membrane in implantation stage endometrium after early luteal phase RU486 treatment in monkeys.
- Published
- 1996
28. Effects of two antiprogestins on early pregnancy in the long-tailed macaque (Macaca fascicularis)
- Author
-
Stephen A. Matlin, Andrew G Hendrickx, Paul F.A. Van Look, Pamela M. Vince, Quin Quin Gu, Charles A.A. Thomas, Bill L. Lasley, and Alice F. Tarantal
- Subjects
medicine.medical_specialty ,Norpregnadienes ,Administration, Oral ,Gestational Age ,Hormone antagonist ,Pregnancy ,Pregnenediones ,Internal medicine ,medicine ,Animals ,Endocrine system ,Progesterone ,Abortifacient ,business.industry ,Abortifacient Agents, Steroidal ,Obstetrics and Gynecology ,Gestational age ,Abortion, Induced ,Mifepristone ,medicine.disease ,Macaca fascicularis ,Endocrinology ,Reproductive Medicine ,Gestation ,Female ,Progestins ,business ,Hormone ,medicine.drug - Abstract
The abortifacient effects of mifepristone and HRP 2000 were compared in gravid long-tailed macaques. Thirty-six animals were studied with treatment administered either by the oral (0.5 or 5.0 mg/kg; N = 5 per antiprogestin per dose) or intramuscular (i.m.) routes (0.5 mg/kg; N = 5 per antiprogestin) on gestational days (GD) 23-26; six vehicle controls were included. Blood samples were collected for assay of progesterone (P4) and each of the antiprogestins (pre-treatment, daily GD 23-28, every other day GD 30-40), and animals were monitored sonographically throughout gestation. Results of these studies indicated high rates of abortion with i.m. administration (3/5 mifepristone, 4/5 HRP 2000) and 5.0 mg/kg oral route (4/5, 2/5, respectively), with less effects noted at oral doses of 0.5 mg/kg (2/5, 0/5, respectively). No early abortions were observed in the control groups. Following daily i.m. treatment, peak levels of 8-16 ng/ml mifepristone were detected whereas 6-10 ng/ ml of HRP 2000 were noted (GD 26-27). No serum levels of mifepristone were detected following either of the oral doses whereas serum levels of 2-6 ng/ml HRP 2000 were noted with high dose oral administratation. Results of these studies suggest: (1) both antiprogestins are roughly comparable in terminating early pregnancy although HRP 2000 may be more efficacious when administered i.m. whereas mifepristone may be more effective when administered orally; (2) similar levels of biological activity are seen with the i.m. and high dose oral dosing regimens, with little or no activity with the oral low dose; and (3) infants resulting from surviving pregnancies were not affected by early gestation exposure.The primary objective was to compare the relative potencies of mifepristone and another newly synthesized antiprogestin, HRP 2000 (17-alpha-acetoxy-11-beta-[4-N,N-dimethylaminophenyl]-pregna-4,9- diene-3,20-dione) in terminating early pregnancy in gravid long-tailed macaques. 36 animals were studied with treatment administered either by the oral (0.5 or 5.0 ng/kg; N = 5 per antiprogestin per dose) or intramuscular (im) routes (0.5 ng/kg; N = 5 per antiprogestin) on gestational days (GD) 23-26; 6 vehicle controls were included. Blood samples were collected for assay of progesterone (P4) and each of the antiprogestins (pre-treatment, daily GD 23-28, every other day GD 30-40), and the animals were monitored sonographically throughout gestation. Results of these studies indicated high rates of abortion with im administration (3/5 mifepristone, 4/5 HRP 2000) and the 5.0 mg/kg oral route (4/5, 2/5, respectively), with less effects noted at oral doses of 0.5 mg/kg (2/5, 0/5, respectively). No early abortions were observed in the control groups. Following daily im treatment, peak levels of 8-16 ng/ml mifepristone were detected, whereas 6-10 ng/ml of HRP 2000 were noted (GD 26-27). No serum levels of mifepristone were detected following either of the oral doses, whereas serum levels of 2-6 ng/ml HRP 2000 were noted with high-dose oral administration. Results of these studies suggest: 1) both antiprogestins are roughly comparable in terminating early pregnancy, although HRP 2000 may be more efficacious when administered im, whereas mifepristone may be more effective when administered orally; 2) similar levels of biological activity are seen with the im and high-dose oral dosing regimens, with little or no activity with the oral low dose; and 3) infants resulting from surviving pregnancies were not affected by early gestation exposure.
- Published
- 1996
29. Development of the definitive kidney in the cynomolgus monkey (Macaca fascicularis)
- Author
-
C. G. Rodriguez, M. A. Cukierski, Andrew G Hendrickx, and N. Makori
- Subjects
Pathology ,medicine.medical_specialty ,Kidney Glomerulus ,Connective tissue ,Renal function ,Gestational Age ,Biology ,Kidney ,urologic and male genital diseases ,law.invention ,Embryonic and Fetal Development ,Pregnancy ,law ,medicine ,Animals ,Metanephrogenic blastema ,General Veterinary ,urogenital system ,Embryo ,Anatomy ,Capillaries ,Macaca fascicularis ,medicine.anatomical_structure ,Ureteric bud ,Female ,Animal Science and Zoology ,Endothelium, Vascular ,Electron microscope - Abstract
Formation of the definitive kidney in Macaca fascicularis embryos was investigated using light and electron microscopy. Appearance of the definitive kidney at stage 14 was indicated by the ureteric bud invading the metanephrogenic blastema. Glomerular capillaries originate from the connective tissue that surrounds the developing renal vesicle. At 46-100 days gestational age the more developed glomeruli show thinning of the capillary endothelium, thickening of the basal membrane, and presence of pedicels, suggesting a capability of renal function.
- Published
- 1996
30. Reproductive toxicity testing of therapeutic biotechnology agents
- Author
-
Narsingh D. Agnish, Judith W. Henck, Ada H. C. Kung, Mercedes Serabian, Kim G. Hilbish, Andrew G Hendrickx, Joyce Mordenti, and Joy A. Cavagnaro
- Subjects
Gerontology ,Embryology ,Anticorps monoclonal ,business.industry ,Health, Toxicology and Mutagenesis ,Medicine ,Toxicology ,business ,Archaeology ,Developmental Biology - Abstract
Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan 48105 (J.WH.); Miles, Inc., Elkhart, Indiana 46515 (K.G.H.); USFDA, Rockville, Maryland 20852 (M.A.S., J.A.C.); California Regional Primate Research Center, Davis, California 95616 (A.G.H.); Hoffman-LaRoche, Inc., Nutley, New Jersey 07110 (N.D.A.); Skyline Technology Consulting Group, Znc., San Francisco, California 94133 (A.H.C.K.); and Genentech, Znc., South San Francisco, California 94080 (J.M.)
- Published
- 1996
31. Frequency of prenatal loss in a macaque breeding colony
- Author
-
Alice F. Tarantal, Tammy A. Hendrie, Jennifer J. Short, Mark I. Hendrie, Eric Rothgarn, Pamela E. Peterson, and Andrew G Hendrickx
- Subjects
Pregnancy ,Incidence (epidemiology) ,Developmental toxicity ,Captivity ,Biology ,Abortion ,medicine.disease ,Macaque ,Measles ,biology.animal ,Immunology ,medicine ,Gestation ,Animal Science and Zoology ,Ecology, Evolution, Behavior and Systematics ,Demography - Abstract
An accurate knowledge of the historical incidence of prenatal loss is essential for management of breeding colonies and for performing developmental toxicity studies in nonhuman primates. Data from the California Regional Primate Research Center indoor (timed-mated) and outdoor (random-mated) colonies of rhesus, cynomolgus, and bonnet macaques (Macaca mulatta, M. fascicularis, and M. radiata) were evaluated for a 10 year breeding period from 1984 to 1993. Pregnancy outcome data for the three species of macaques summarized in this report indicate that early pregnancy as well as term are vulnerable periods of gestation in terms of prenatal loss. Prematurity as well as twinning were additionally associated with elevated rates of loss during the prenatal or neonatal period. The incidence of pregnancy failure did not appear to be related to different housing/management conditions (i.e., indoor timed-mated vs. outdoor random-mated), parity, animal handling, shipping, or relocation. Some of the annual fluctuations in abortions could be related to disease outbreaks (e.g., measles, pneumonia) in the colony. These data will be invaluable in planning for research needs which focus on developmental biology and perinatology, and in interpreting the significance of abortions following exposure to experimental agents in small numbers of animals. © 1996 Wiley-Liss, Inc.
- Published
- 1996
32. Developmental Zinc Deficiency and Behavior
- Author
-
Mari S. Golub, Andrew G Hendrickx, M. Eric Gershwin, and Carl L. Keen
- Subjects
medicine.medical_specialty ,Calorie ,Central nervous system ,Medicine (miscellaneous) ,chemistry.chemical_element ,Zinc ,Biology ,Embryonic and Fetal Development ,Lethargy ,Emotionality ,Internal medicine ,medicine ,Animals ,Humans ,Behavior ,Nutrition and Dietetics ,Brain ,Micronutrient ,medicine.disease ,Malnutrition ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Zinc deficiency ,Deficiency Diseases - Abstract
The majority of studies of developmental zinc deficiency and behavior were conducted in laboratory animals, primarily rats and rhesus monkeys. Effects on food intake complicate interpretation of experiments using severe zinc deficiency. Severe zinc deficiency in rats during the period of rapid brain growth has similar effects to protein calorie malnourishment during this period, including altered emotionality and food motivation. When behavior is tested during a period of zinc deprivation in immature animals, lethargy (reduced activity and responsiveness) is a prominent characteristic, but learning, attention and memory are also affected. The few supplement studies available in children did not report effects on behavior. Although zinc has multiple roles in brain function, considerable brain sparing occurs in zinc deficiency, and peripheral mechanisms of altered behavior also need to be considered.
- Published
- 1995
33. Localization of integrin subunits ?6 and ?1 during somitogenesis in the long-tailed macaque (M. fascicularis)
- Author
-
C. S.T. Pow and Andrew G Hendrickx
- Subjects
Integrins ,Histology ,Integrin beta1 ,Immunocytochemistry ,Integrin ,Cell Biology ,Integrin alpha6 ,Biology ,Immunohistochemistry ,Molecular biology ,Pathology and Forensic Medicine ,Embryonic and Fetal Development ,Somite ,medicine.anatomical_structure ,Laminin ,Myotome ,Somitogenesis ,medicine ,biology.protein ,Animals ,Macaca ,Myocyte ,Basal lamina - Abstract
The distribution of integrin subunits alpha 6 and beta 1, and the alpha 6 beta 1 integrin ligand, laminin, was examined during somitogenesis in developmental stages 11, 13, and 16 in the long-tailed macaque, using peroxidase immunocytochemistry. Within differentiating somites in stage 11, alpha 6 expression was observed in the sclerotome, basal surface of dermamyotomal cells adjacent to the basal lamina and on scattered cells throughout the dermamyotome. In further advanced somites in stages 13 and 16, alpha 6 immunoreactivity became restricted to the myotome. alpha 6 was expressed on mesenchymal core cells within the myocele of undifferentiated epithelioid somites and the ventromedial wall of somites commencing differentiation at each stage. beta 1 distribution resembled that of alpha 6 in stage 11 somitic tissue, however, it remained present on myotome and sclerotome cells in the later stages, and was also expressed on dermatomal cells in stage 16. Laminin immunoreactivity, while more intense and prevalent than alpha 6 and beta 1 in each stage examined, occurred on the same somite cell populations as the 2 integrin subunits. These results show a defined distribution of alpha 6 on somitic tissue, and suggest this integrin is involved in somite differentiation. They also support a possible role for alpha 6 in myoblast formation and migration. Overlapping of beta 1 and laminin immunoreactivity with that of alpha 6 further suggests that alpha 6 pairs with beta 1 as a functional heterodimer for laminin in defined somitic regions.
- Published
- 1995
34. Extracellular superoxide dismutase activity is affected by dietary zinc intake in nonhuman primate and rodent models
- Author
-
M E Gershwin, Katherine L. Olin, Carl L. Keen, Mari S. Golub, Bo Lönnerdal, and Andrew G Hendrickx
- Subjects
Male ,medicine.medical_specialty ,Nutritional Status ,Medicine (miscellaneous) ,chemistry.chemical_element ,Zinc ,Models, Biological ,Rats, Sprague-Dawley ,Superoxide dismutase ,Internal medicine ,medicine ,Extracellular ,Animals ,chemistry.chemical_classification ,Nutrition and Dietetics ,biology ,Superoxide Dismutase ,medicine.disease ,Macaca mulatta ,Enzyme assay ,In vitro ,Diet ,Rats ,Cytosol ,Enzyme ,Endocrinology ,chemistry ,Zinc deficiency ,biology.protein ,Female - Abstract
Assessment of zinc nutriture is often compromised by the lack of reliable biomarkers. In the present study the effect of dietary zinc deprivation on plasma extracellular superoxide dismutase (EC SOD) activity was investigated in rat and rhesus macaque models. This enzyme, which contains both zinc and copper, is distinct from cytosolic copper-zinc SOD. Young, growing rats fed zinc-deficient diets (1.5 nmol Zn/g diet) were characterized by low plasma zinc concentrations and plasma EC SOD activities (16% and 56% of controls, respectively). Adolescent rhesus macaques fed diets that contained a marginal amount of zinc (30.6 nmol Zn/g diet) also had low plasma zinc concentrations and low EC SOD activities compared with controls fed diets containing 765 nmol Zn/g diet (75% and 40%, respectively). Enzyme activity was not affected after in vitro addition of zinc to plasma samples from control, restrict-fed, and zinc-deficient rats. Taken together, these data support the concept that plasma EC SOD activity can be a biomarker for zinc status. Am J Clin Nutr 1995 ;61 :1263-7.
- Published
- 1995
35. Hematologic and growth-related effects of frequent prenatal ultrasound exposure in the long-tailed macaque (Macaca fascicularis)
- Author
-
Sharron E. Gargosky, Andrew G Hendrickx, Alice F. Tarantal, William D. O'Brien, and D.S. Ellis
- Subjects
medicine.medical_specialty ,Neutropenia ,Acoustics and Ultrasonics ,Birth weight ,Biophysics ,Bone Marrow Cells ,Gestational Age ,Growth ,Ultrasonography, Prenatal ,Andrology ,Embryonic and Fetal Development ,Bone Marrow ,Insulin-Like Growth Factor II ,Pregnancy ,Internal medicine ,medicine ,Animals ,Birth Weight ,Cell Lineage ,Radiology, Nuclear Medicine and imaging ,Insulin-Like Growth Factor I ,Progenitor cell ,Fetus ,Hematology ,Radiological and Ultrasound Technology ,Cesarean Section ,business.industry ,Body Weight ,Temperature ,Granulocyte-Macrophage Colony-Stimulating Factor ,Gestational age ,Fetal Blood ,Hematopoietic Stem Cells ,medicine.disease ,Blood Cell Count ,Macaca fascicularis ,Insulin-Like Growth Factor Binding Protein 3 ,medicine.anatomical_structure ,Immunology ,Gestation ,Female ,Bone marrow ,business - Abstract
Prior investigations have shown that reduced birth weights and transient neutropenias result from frequent exposure of monkey fetuses to ultrasound. To further explore these findings, 26 animals were studied (16 exposed, 10 controls; "triple mode"; ATL Ultramark 9 with HDI; ISPTAd approximately 645 to 714 mW/cm2). Exposures were performed daily for 5 days each week from gestational days (GD) 21 to 35 (5 min), three times weekly from GD 36 to 60 (5 min), then weekly from GD 61 to 153 +/- 1 (10 min). Fetal blood samples (FBS) were collected for complete blood counts (CBCs), hematopoietic progenitor assay, circulating insulin-like growth factors (IGF-I, IGF-II) and binding proteins (IGFBP-3) (GD 120, 140, 153 +/- 1). Animals were delivered by Cesarean section at term (GD 153 +/- 1), and body weights, morphometrics, CBCs, and bone marrow aspirates assessed at delivery and postnatally for 3 months. Fetal neutropenias were noted in exposed animals in addition to reduced circulating progenitors (colony forming unit-granulocyte-macrophage [CFU-GM]). Growth of CFU-GM from bone marrow was exuberant at term, whereas circulating levels were diminished comparable to prenatal samples. Exposed animals were smaller at birth; marked reductions in IGFBP-3 were noted prenatally. These data suggest that frequent prenatal ultrasound exposure can transiently alter the neutrophil lineage, although these findings may be the result of enhanced margination and organ sequestration. Data also suggest that transient, altered growth patterns may be due to perturbations of the IGF axis.
- Published
- 1995
36. Nicotine- or epinephrine-induced uteroplacental vasoconstriction and fetal growth in the rat
- Author
-
Samuel C. Birnbaum, null Nguyen Kien, Richard W. Martucci, Thomas R. Gelzleichter, Hanspeter Witschi, Andrew G. Hendrickx, and Jerold A. Last
- Subjects
Nicotine ,medicine.medical_specialty ,Epinephrine ,Placenta ,Uterus ,Toxicology ,Rats, Sprague-Dawley ,Embryonic and Fetal Development ,Fetus ,Pregnancy ,Internal medicine ,Animals ,Medicine ,Placental Circulation ,Cotinine ,Maternal-Fetal Exchange ,business.industry ,Infusion Pumps, Implantable ,Rats ,Endocrinology ,medicine.anatomical_structure ,Vasoconstriction ,Catecholamine ,Gestation ,Female ,medicine.symptom ,business ,medicine.drug - Abstract
We examined the relationship between nicotine-induced vasoconstriction in pregnant rat dams and fetal growth during the third trimester of pregnancy. Pregnant rats were continuously treated between days 13 and 19 of gestation with either nicotine (9.6, 4.8 or 2.4 mg/kg/day), epinephrine (0.72 microgram/kg/day), or saline via continuous infusion from a subcutaneously implanted osmotic minipump. Placental weights in rats treated with high dose nicotine and dams' body weights were severely reduced. However, fetal weights were not affected. Blood flows in uterus and placenta were quantified by measurement of tissue content of 85Sr-labelled microspheres injected via a carotid artery catheter. Both nicotine and epinephrine caused a significant reduction (> 40%) in uterine and placental blood flow. We conclude that vasoconstriction alone as a result of nicotine or epinephrine administration during the last trimester of gestation does not necessarily reduce nutrient supply to the fetus and does not affect fetal growth in rats.
- Published
- 1994
37. Intravaginal inoculation of rhesus macaques with cell-free simian immunodeficiency virus results in persistent or transient viremia
- Author
-
Nancy J. Alexander, Christopher J. Miller, Andrew G Hendrickx, John P. Moore, Marta L. Marthas, Judith Torten, and Gustavo F. Doncel
- Subjects
Male ,animal diseases ,viruses ,Immunology ,Simian Acquired Immunodeficiency Syndrome ,Enzyme-Linked Immunosorbent Assay ,Viremia ,medicine.disease_cause ,Microbiology ,Macaque ,Peripheral blood mononuclear cell ,Monocytes ,Virus ,Immune system ,Semen ,Virology ,biology.animal ,medicine ,Animals ,Humans ,Seroconversion ,Antigens, Viral ,Cell-Free System ,biology ,virus diseases ,Simian immunodeficiency virus ,medicine.disease ,Macaca mulatta ,Simian AIDS ,Insect Science ,Vagina ,Female ,Simian Immunodeficiency Virus ,Lymph Nodes ,Research Article - Abstract
The simian immunodeficiency virus (SIV)-rhesus macaque model of heterosexual human immunodeficiency virus transmission consists of atraumatic application of cell-free SIVmac onto the intact vaginal mucosa of mature female rhesus macaques. This procedure results in systemic infection, and eventually infected animals develop the clinical signs and pathologic changes of simian AIDS. To achieve 100% transmission with the virus stocks used to date, multiple intravaginal inoculations are required. The current titration study utilized two stocks of SIVmac and demonstrated that a single intravaginal dose of cell-free SIV can reliably produce infection in rhesus macaques. This study also demonstrated that some animals intravaginally inoculated with cell-free SIVmac develop transient viremia characterized by a limited ability to isolate virus from peripheral blood mononuclear cells and lymph node mononuclear cells and no seroconversion to SIV antigen. SIV could be isolated from the peripheral lymph nodes of transiently viremic animals only during periods of viremia and not at times when SIV was not detected in circulating mononuclear cells. Thus, peripheral lymphoid tissues were not reservoirs of infection in the transiently viremic animals. Taken together, these results suggest either that the SIV infection was cleared in the transiently viremic animals or that SIV infection is limited to a compartment of the genital mucosal immune system that cannot be assessed by monitoring SIV infection in peripheral blood mononuclear cells and peripheral lymphoid tissue.
- Published
- 1994
38. Modulation of behavioral performance of prepubertal monkeys by moderate dietary zinc deprivation
- Author
-
P T Takeuchi, Carl L. Keen, M E Gershwin, Bo Lönnerdal, Mari S. Golub, and Andrew G Hendrickx
- Subjects
Male ,Taste ,medicine.medical_specialty ,Iron ,Period (gene) ,Medicine (miscellaneous) ,chemistry.chemical_element ,Growth ,Zinc ,Motor Activity ,Dietary zinc ,Internal medicine ,medicine ,Animals ,Sexual maturity ,Sexual Maturation ,Motor activity ,Nutrition and Dietetics ,Behavior, Animal ,business.industry ,medicine.disease ,Macaca mulatta ,Crossover study ,Endocrinology ,chemistry ,Zinc deficiency ,Female ,business ,Copper - Abstract
Young rhesus monkeys (Macaca mulatta, n = 14) 25-30 mo of age were fed a zinc-deficient (ZD) diet (2 micrograms Zn/g diet) (moderate zinc deprivation) over 15 week. The ZD diet period was compared with a zinc-adequate (ZA) diet period (50 micrograms Zn/g diet) of the same duration, which either preceded or followed it (crossover design). Plasma zinc was lower at the end of the ZD than after the ZA period. There were no overt signs of zinc deficiency or effects on growth rate. Spontaneous motor activity was lower and performance of a visual-attention task and short-term-memory task were poorer during the ZD period than during the ZA period. Behavioral effects were detected as changes from individual baseline values, and often represented a failure to improve. The results suggests that dietary zinc deprivation can modulate behavior in prepubertal monkeys without affecting growth.
- Published
- 1994
39. Effects of exposure to nicotine and to sidestream smoke on pregnancy outcome in rats
- Author
-
Hanspeter Witschi, Sara M. Lundgaard, Padmanabhan Rajini, Andrew G. Hendrickx, and Jerold A. Last
- Subjects
Litter (animal) ,Nicotine ,Passive smoking ,Litter Size ,Physiology ,Administration, Cutaneous ,Toxicology ,medicine.disease_cause ,Rats, Sprague-Dawley ,Embryonic and Fetal Development ,Pregnancy ,Animals ,Medicine ,Sidestream smoke ,Continuous exposure ,Transdermal ,business.industry ,Pregnancy Outcome ,General Medicine ,medicine.disease ,Rats ,Anesthesia ,Toxicity ,Female ,Tobacco Smoke Pollution ,business ,medicine.drug - Abstract
Nicotine-delivering transdermal patches were applied to the back of timed-pregnant Sprague-Dawley rats. Pregnancy failure was 100% in animals exposed to 3.5 mg of nicotine per day during the entire pregnancy and 50% in animals exposed to the same amount during the first trimester. Application of 1.75 mg of nicotine per day resulted in a 50% pregnancy failure when exposure occurred during the entire pregnancy. In animals exposed for the first half of pregnancy to cigarette sidestream smoke, under conditions where plasma nicotine levels reached about 25% of those observed following exposure to 1.75 mg of nicotine per day, the average litter size was reduced by about 25%. It is concluded that continuous exposure to nicotine early during pregnancy may adversely affect pregnancy outcome in rats.
- Published
- 1994
40. Infant mortality: The role of the macaque as a model for human disease
- Author
-
Alice F. Tarantal and Andrew G Hendrickx
- Subjects
biology ,business.industry ,Mechanism (biology) ,Fetal alcohol syndrome ,Sudden infant death syndrome ,medicine.disease ,Bioinformatics ,Macaque ,Sudden death ,Infant mortality ,Transplantation ,Malnutrition ,biology.animal ,medicine ,Animal Science and Zoology ,business ,Ecology, Evolution, Behavior and Systematics - Abstract
Factors which have been identified as the leading causes of infant mortality include birth defects, hemoglobinopathies, prematurity, and Sudden Infant Death Syndrome (SIDS). In order to further our understanding of the specific causes of infant mortality and the mechanisms by which they occur, suitable animal models will be required. Studies with nonhuman primates (specifically the macaque) have addressed malformation/functional deficit syndromes such as those associated with Fetal Alcohol Syndrome (FAS), nutritional deficiencies, and retinoid teratogenicity. These studies have provided critical information for further basic and preventive research. In addition, efforts to evaluate the safety of diagnostic ultrasound continue to aid in identifying safe methods for exposure. From a prenatal perspective, cellular transplantation has been shown to be a feasible method for treating individuals with inherited defects in utero, thereby avoiding postnatal transplantation and the associated risks. Longterm complications of prematurity have also been pursued with growth factors (i.e., epidermal growth factor) noted to play an important role in both pre- and postnatal development of the gastrointestinal tract and lung. As one of the most distressing causes of death in infancy, SIDS will require a concentrated effort to understand the basic mechanism(s) responsible for the characteristic respiratory complications. The nonhuman primate will continue to provide critical information as the model of choice for the human in determining the causes, mechanisms, and treatments for these significant causes of infant death. © 1994 Wiley-Liss, Inc.
- Published
- 1994
41. Maternal Dietary Zinc Influences DNA Strand Break and 8-Hydroxy-2'-Deoxyguanosine Levels in Infant Rhesus Monkey Liver
- Author
-
Bruce N. Ames, M E Gershwin, Golub Ms, Katherine L. Olin, Andrew G Hendrickx, Carl L. Keen, and Shigenaga Mk
- Subjects
medicine.medical_specialty ,Antioxidant ,DNA damage ,DNA repair ,medicine.medical_treatment ,chemistry.chemical_element ,Zinc ,Biology ,General Biochemistry, Genetics and Molecular Biology ,chemistry.chemical_compound ,Pregnancy ,Internal medicine ,medicine ,Animals ,Deoxyguanosine ,8-Hydroxy-2'-deoxyguanosine ,medicine.disease ,Macaca mulatta ,Diet ,Surgery ,Endocrinology ,Liver ,chemistry ,8-Hydroxy-2'-Deoxyguanosine ,Prenatal Exposure Delayed Effects ,Zinc deficiency ,Female ,DNA ,DNA Damage - Abstract
Severe zinc deficiency in rodent models has been shown to influence the frequency of single-strand breaks in DNA isolated from liver. In the current study, we investigated whether DNA isolated from infant monkeys born to mothers fed zinc-restricted diets would be characterized by higher than normal levels of DNA damage. DNA was isolated from 30-day-old infants born to dams fed low zinc (2 or 4 micrograms Zn/g) or control zinc (50 micrograms Zn/g) diets. The amount of single-strand breaks in liver DNA was significantly higher in the low zinc group than in controls; consistent with the above, there was a trend for higher steady state levels of liver 8-hydroxy-2'-deoxyguanosine in the low zinc group. While evidence for DNA damage in the low zinc group was obtained, the activities of several antioxidant enzymes were similar between the low zinc and control groups. In summary, infants born to monkeys fed low zinc diets are characterized by evidence of DNA damage shortly after birth; this damage may be due to an increased rate of oxidative damage and/or a reduction in the rate of DNA repair.
- Published
- 1993
42. Sonographic heat generation in vivo in the gravid long-tailed macaque (Macaca fascicularis)
- Author
-
W. D. O'Brien, Alice F. Tarantal, F. Chu, and Andrew G Hendrickx
- Subjects
Male ,Pulse repetition frequency ,Hot Temperature ,Gestational Age ,Third trimester ,Ultrasonography, Prenatal ,Body Temperature ,Long-tailed macaque ,Fetus ,Pregnancy ,Reference Values ,In vivo ,Animals ,Medicine ,Radiology, Nuclear Medicine and imaging ,Pulsed doppler ,Radiological and Ultrasound Technology ,business.industry ,Ultrasound ,Anatomy ,Macaca fascicularis ,Heat generation ,Pregnancy, Animal ,Female ,Ultrasonic sensor ,business ,Nuclear medicine - Abstract
Temperature elevations that occur during diagnostic ultrasonic exposure were assessed in vivo in gravid macaques after 10, 20, or 30 min (scan mode; N = 30) or 5, 10, or 15 min (pulsed Doppler; N = 32). Five time points were assessed during the second and third trimesters (gestational days 70 to 150 +/- 2; term, approximately 165 days) using a transient thermocouple technique. Measurements were obtained intracranially or at the muscle-bone interface using a commercial sector scanner (ATL MK 600, 7.5 MHz scanhead; scan mode, ISPTA) = 27 mW/cm2, ISPPA = 85 W/cm2, pulse repetition frequency (PRF) = 1 kHz; pulsed Doppler - ISPTA = 54 mW/cm2, ISPPA = 1.5 W/cm2, PRF = 18.5 kHz). Overall, the greatest temperature elevation achieved with either modality or location was 0.6 degrees C.
- Published
- 1993
43. Effect of the Severity of Maternal Zinc Deficiency on Pregnancy Outcome and Infant Zinc Status in Rhesus Monkeys
- Author
-
Andrew G Hendrickx, Katherine L. Olin, Janet Y. Uriu-Hare, T. W. Graham, M. Eric Gershwin, Bo Lönnerdal, Carl L. Keen, and Mari S. Golub
- Subjects
medicine.medical_specialty ,Nutritional Status ,chemistry.chemical_element ,Zinc ,Biology ,Pregnancy ,Internal medicine ,Lactation ,medicine ,Animals ,Metallothionein ,Maternal-Fetal Exchange ,Fetus ,Pregnancy Outcome ,medicine.disease ,Macaca mulatta ,Diet ,Endocrinology ,medicine.anatomical_structure ,Animals, Newborn ,chemistry ,Pediatrics, Perinatology and Child Health ,Zinc deficiency ,Gestation ,Female ,Breast feeding - Abstract
To investigate the effects of the severity of maternal zinc deficiency on early development, rhesus monkeys were fed diets that were either moderately zinc-deficient (MZD) (2 μg Zn/g) or marginal in zinc (M) (4 μg Zn/g throughout pregnancy and lactation. Dams in the MZD group developed overt signs of zinc deficiency. Compared with control dams fed diets adequate in zinc (C) (50 or 100 μg Zn/g), both M and MZD dams showed low mitogen response. Pregnancy outcome was similar in all groups, and infants were considered healthy at delivery. From birth until d 30, infants were closely monitored for signs of zinc deficiency. On d 30, infants were killed and tissues were analyzed for several parameters reported to be affected by zinc status. MZD infants tended to have lower plasma zinc concentrations than C infants, although the difference was only significant at d 14. M infants tended to have lower plasma zinc concentrations than C infants. Mitogen response was lower in MZD and M infants than in C infants. However, mitogen responses were similar in MZD and M infants. Liver zinc concentrations were similar among the three groups of infants; however, zinc and metallothionein concentrations in (10 000 × g) liver supernatant fractions were lower in the MZD and M groups than in the C group. 65Zn absorption/retention was higher in MZD and M mothers and infants than in C mothers and infants; there were no marked differences between MZD and M mothers or infants. In contrast to whole-body absorption, 65Zn uptake/retention by isolated hepatocytes was similar among the three infant groups. Plasma metallothionein concentrations were higher in the MZD mothers during the 1st, 2nd, and 3rd trimester than in the M or C mothers and higher than C mothers on d 30 postpartum; plasma metallothionein concentrations were similar among the three groups of infants. These results demonstrate that feeding a diet containing 2 μg Zn/g to rhesus monkeys during pregnancy and lactation results in marked signs of zinc deficiency, whereas feeding a diet containing 4 μg Zn/g results in only subtle signs.
- Published
- 1993
44. Assessment of the Developmental Toxicity of 2-Ethylhexanoic Acid in Rats and Rabbits
- Author
-
Andrew G Hendrickx, M. F. Kubena, M. A. Vrbanic, Rochelle W. Tyl, L. J. Fosnight, L. C. Fisher, Pamela E. Peterson, and Gary V. Katz
- Subjects
Male ,medicine.medical_specialty ,No-observed-adverse-effect level ,Developmental toxicity ,Physiology ,Toxicology ,Fetus ,Pregnancy ,Oral administration ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Caproates ,Dose-Response Relationship, Drug ,business.industry ,Body Weight ,Maternal effect ,Abnormalities, Drug-Induced ,medicine.disease ,Rats, Inbred F344 ,Teratology ,Rats ,Endocrinology ,Toxicity ,Female ,Maternal death ,Rabbits ,business ,Hypoactivity - Abstract
Assessment of the Developmental Toxicity of 2-Ethylhexanoic Acid in Rats and Rabbits. Hendrickx, A. G., Peterson, P. E., Tyl, R. W., Fisher, L. C., Fosnight, L. J., Kubena, M. F., Vrbanic, M, A., and Katz, G, V, (1993). Fundam. Appl. Toxicol. 20, 199-209. This study was carried out to assess the developmental toxicity of orally administered 2-ethylhexanoic acid (2-EHA) throughout organogenesis in the rat and the rabbit. Treatment of Fischer 344 inbred rats with doses of 100 to 1000 mg 2-EHA/ kg/day on (Gestation Days) (GD) 6-15 in a range-finding and a definitive study resulted in a high level of maternal death at 1000 mg/kg/day. Clinical signs of maternal toxicity, including increased liver weight, as well as increased resorptions, dead fetuses, and growth retardation, but no malformations, were observed at 500 mg/kg/day. Slight developmental toxicity, manifested as a reduction in skeletal ossification, occurred in fetuses exposed to 250 mg/kg/day. No adverse effects of treatment were associated with the lower 2-EHA doses (100 and 125 mg/kg/ day). Maternal toxicity was also observed in range-finding and definitive studies in New Zealand white rabbits exposed to 25 to 1000 mg 2-EHA/kg/day on GD 6-18 with excessive mortality observed at the highest doses (500 and 1000 mg/kg/day). A low incidence of maternal death as well as abortion occurred following treatment with 125 and 250 mg 2-EHA/kg/day. Less severe clinical signs (reduced weight and food consumption and hypoactivity) were also observed in the 250 mg/kg/day group. There were no adverse effects on fetal viability, growth, or morphology at any dose level. Thus, exposure to 2-EHA during the entire period of organogenesis caused developmental toxicity only at maternally toxic doses in the rat or adverse maternal effects in the absence of developmental toxicity in the rabbit. No evidence of teratogenicity was associated with 2-EHA in this classical safety assessment regimen in either species. The no observed adverse effect levels (NOAELs) for maternal and developmental toxicities in rats are 250 and 100 mg/kg/day, respectively; the corresponding NOAELs for rabbits are 25 mg/kg/day (maternal) and ⩾250 mg/kg/day (developmental).
- Published
- 1993
45. Characterization of the Extracellular Matrix during Somitogenesis in the Long-Tailed Monkey (Macaca fascicularis)
- Author
-
Pamela E. Peterson, Andrew G Hendrickx, C. S.T. Pow, and Doris B. Wilson
- Subjects
Basement membrane ,Histology ,biology ,Immunocytochemistry ,Matrix (biology) ,Cell biology ,Fibronectin ,Extracellular matrix ,Somite ,medicine.anatomical_structure ,Biochemistry ,Laminin ,Somitogenesis ,medicine ,biology.protein ,Anatomy - Abstract
The composition of the extracellular matrix (ECM) associated with somitogenesis (stages 10–14) in the long-tailed monkey (Macaca fascicularis) was examined using peroxidase immunocytochemistry. A distinct temporal and spatial staining pattern was demonstrated for each component examined. Fibronectin (FN), laminin (LM) and hyaluronic acid (HA) were associated with the somite at each developmental stage, while no chondroitin sulfate (CS) staining was evident until stages 13/14. The basement membrane and matrix fibers linking the somites to the surrounding epithelia stained for FN, LM and HA. Localization of LM and HA between somite cells was observed at each stage, whereas FN and CS reactivity within the somitic tissue was only observed between sclerotome cells at stages 13/14. Whereas FN- and HA-positive fibers surrounded the unsegmented mesoderm, HA, and to a lesser extent LM, were located within the pre-somitic tissue. Comparisons are made with earlier studies conducted in rodent and avian embryos which indicate that these ECM components may play a regulatory role in primate somitogenesis.
- Published
- 1993
46. Contents, Vol. 146, 1993
- Author
-
A. Atasever, H. Hamdi Çelik, Y. Yamamoto, D.M. Serlin, T. Yamashita, C. S.T. Pow, Doris B. Wilson, Pamela E. Peterson, N. Kitamura, Andrew G Hendrickx, B. Durgun, C.R. Braekevelt, M.H. Schieber, A. Boros, J.A. Trotter, J. Yamada, É. Fekete, and Engin Yilmaz
- Subjects
Histology ,Anatomy - Published
- 1993
47. Measurement of periimplantational relaxin concentrations in the macaque using a homologous assay
- Author
-
Bill L. Lasley, James W. Overstreet, Richard Stouffer, Dennis R. Stewart, and Andrew G Hendrickx
- Subjects
endocrine system ,medicine.medical_specialty ,media_common.quotation_subject ,Heterologous ,Enzyme-Linked Immunosorbent Assay ,Luteal Phase ,Luteal phase ,Biology ,Macaque ,Endocrinology ,Corpus Luteum ,Pregnancy ,biology.animal ,Internal medicine ,medicine ,Animals ,Embryo Implantation ,Progesterone ,Menstrual cycle ,media_common ,Relaxin ,urogenital system ,Progesterone secretion ,Venous blood ,Macaca mulatta ,Trophoblasts ,body regions ,Macaca fascicularis ,Methotrexate ,Female ,hormones, hormone substitutes, and hormone antagonists ,Hormone - Abstract
Circulating relaxin concentrations in the human rise in the late luteal phase and increase further in response to increasing circulating CG concentrations immediately after implantation. Similar events have not been documented in the laboratory macaque because of the lack of sensitivity of heterologous assay systems. A homologous enzyme-linked immunosorbent assay for authentic macaque relaxin was developed and validated. Using this enzyme-linked immunosorbent assay, relaxin concentrations were measured in peripheral and ovarian venous blood collected from cynomolgus and rhesus macaques. Relaxin concentrations rose in the late luteal phase of nonconceptive menstrual cycles in cynomolgus macaques, but it was not detected at other times in the cycle. In conceptive cycles, relaxin concentrations rose rapidly in close association with the appearance of mCG 13-14 days after mating. Pregnant rhesus macaques also had elevated relaxin concentrations in blood samples collected on days 15-17 postbreeding. Relaxin concentrations disappeared immediately after luteectomy or ablation of the trophoblast by either surgery or administration of methotrexate. The rise of relaxin paralleled the rise of mCG until 20-25 days postbreeding, while progesterone concentrations declined during this same time period. The lack of correlation between relaxin and progesterone secretion profiles suggests that either the cellular origins or the intracellular mechanisms promoting the secretion of these hormones are different. The periimplantational profile of serum relaxin in macaques was similar to the profile of relaxin observed during early human pregnancy.
- Published
- 1993
48. An updated history of the Teratology Society
- Author
-
Mason Barr, John M. Rogers, Andrew G Hendrickx, William J. Scott, Robert L. Brent, Godfrey P. Oakley, D. M. Kochhar, and Thomas H. Shepard
- Subjects
Gerontology ,Teratology ,Embryology ,Medical education ,medicine.medical_specialty ,business.industry ,Research areas ,media_common.quotation_subject ,Alternative medicine ,MEDLINE ,Continuing education ,General Medicine ,Politics ,Pediatrics, Perinatology and Child Health ,Medicine ,Social content ,business ,Societies, Medical ,Developmental Biology ,Diversity (politics) ,media_common - Abstract
BACKGROUND: The 49-year history of the Teratology Society is reviewed. An abbreviated history is outlined in table form, with listings of the Warkany Lectures, the Continuing Education Courses, and officers of the society. The original article was updated to include the years 2000 to 2010. METHODS: A year-by-year description of the events is given, including the scientific and social content of the annual meetings and changes in the business of the society, in many cases using comments from the past presidents. The valuable and unique diversity of the members is discussed and illustrated, presenting the disciplines and main research areas of the presidents. The number of submitted abstracts and the various categories are tabulated, averaging the number and type over successive periods. A significant increase in the number of abstracts dealing with epidemiology and developmental biology is evident. The society’s development is compared to that of a human, and the question was asked by Shephard et al. (2000): Have we reached the maturational stage of old age or senescence, or is the society still maturing gracefully? This question needs further discussion by all the members. By 2010, many positive changes are happening to revitalize the society. RESULTS: During the past 50 years, we have developed the scientific basis to prevent birth defects caused by rubella, alcoholism, and folate deficiency, as well as other prenatal exposures. We are now taking advantage of advances in many fields to begin shaping the Teratology Society of the 21st century. CONCLUSIONS: We must now engage in political battles to obtain the resources needed to conduct further research and to implement prevention programs, as well as to provide care and rehabilitation for persons with birth defects. Birth Defects Research (Part A) 88:263–285, 2010. 2010 Wiley-Liss, Inc.
- Published
- 2010
49. Embryotoxicity studies of norfloxacin in cynomolgus monkeys. II. Role of progesterone
- Author
-
Mark A. Cukierski, Alice F. Tarantal, R. Tarara, Bill L. Lasley, R. T. Robertson, David L. Hess, Srinivasa Prahalada, Andrew G Hendrickx, and Chennekatu P. Peter
- Subjects
Embryology ,medicine.medical_specialty ,Health, Toxicology and Mutagenesis ,media_common.quotation_subject ,Gestational Age ,Biology ,Luteal phase ,Toxicology ,Chorionic Gonadotropin ,Excretion ,Corpus Luteum ,Pregnancy ,Oral administration ,Internal medicine ,medicine ,Animals ,Fetal Death ,Progesterone ,Norfloxacin ,Menstrual cycle ,media_common ,Estradiol ,Teratology ,Macaca fascicularis ,medicine.anatomical_structure ,Endocrinology ,Toxicity ,Female ,Corpus luteum ,Developmental Biology ,medicine.drug - Abstract
Norfloxacin, an orally active fluoroquinolone antimicrobial, has been reported to be embryolethal but not teratogenic when administered to pregnant cynomolgus macaques prior to gestational day (GD) 36 at doses ≤200 mg/kg/day. Additional studies have been performed in an effort to examine the mechanism responsible for this effect, particularly regarding the role of progesterone (P). The first study (Study I) investigated the effect of norfloxacin administration during early pregnancy (200 mg/kg/day; daily GD 20–30) in the absence of a functional corpus luteum (CL). The CL was surgically removed from 16 gravid females on GD 19 in order to focus on placental-derived P; ten were dosed with norfloxacin and six received vehicle only. Embryolethality was observed for 7/10 (70%) of the treated animals during GD 25–31 versus 0/6 (0%) for controls. A reduction in serum P was noted prior to embryonic loss, although no significant effects on chorionic gonadotropin (CG), 17β-estradiol (E2), or P or E urinary metabolites were observed. A second study (Study II) was performed in order to evaluate the capacity of norfloxacin (200 mg/kg) to reduce CL-derived P in both normally cycling and CG-stimulated nonpregnant females (ten treated, ten controls; daily for 8 days). No effects on P production or on luteal phase or menstrual cycle lengths were observed. The third study (Study III) was designed to examine the effect of norfloxacin on the metabolism and excretion of P in nonpregnant females. Silastic P implants were placed subcutaneously in order to maintain constant P levels during a 10 day treatment regimen (200 mg/kg/day; ten controls, nine treated). Five of the controls and four of the norfloxacin-treated females also received 14C-P intravenously within 1 hr of the last dose of norfloxacin in order to study excretory patterns. No significant differences between control and treated groups were observed. The results of these studies combined suggest that the developmental toxic effects observed in prior studies and Study I are specific to pregnancy and directly related to placental-derived P production. © 1992 Wiley-Liss, Inc.
- Published
- 1992
50. The Baboon in Embryology and Teratology Research
- Author
-
Andrew G Hendrickx and Pamela E. Peterson
- Subjects
Triamcinolone acetonide ,biology ,business.industry ,Zoology ,Rubella virus ,Anatomy ,medicine.disease_cause ,Cynomolgus macaque ,Teratology ,medicine.anatomical_structure ,biology.animal ,Embryology ,medicine ,Nasal septum ,business ,Baboon ,medicine.drug - Published
- 2009
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