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International audience; In recent years, the zebrafish has become a well-established laboratory model. We describe here the ZeBraInspector (ZBI) platform for high-content 3D imaging (HCI) of 5 days post-fertilization zebrafish eleuthero-embryos (EEs). This platform includes a mounting method based on 3D-printed stamps to create a grid of wells in an agarose cast, facilitating batch acquisitions with a fast-confocal laser scanning microscope. We describe reference labeling in cleared fish with a fluorescent lipophilic dye. Based on this labeling, the ZBI software registers. EE 3D images, making it possible to visualize numerous identically oriented EEs on a single screen, and to compare their morphologies and any fluorescent patterns at a glance. High-resolution 2D snapshots can be extracted. ZBI software is therefore useful for diverse high-content analyses (HCAs). Following automated segmentation of the lipophilic dye signal, the ZBI software performs volumetric analyses on whole EEs and their nervous system white matter. Through two examples, we illustrate the power of these analyses for obtaining statistically significant results from a small number of samples: the characterization of a phenotype associated with a neurodevelopmental mutation, and of the defects caused by treatments with a toxic anti-cancer compound.

Contains fulltext : 287837.pdf (Publisher’s version ) (Open Access) The Medical School of Padua (Italy) contributed profoundly to the study of teratology. Many famous physicians and professors of medicine, such as Liceti, Vallisneri, Morgagni, and Malacarne, have studied and investigated these anomalies to better understand the causes and to find a potential explanation, often preserving the specimens for future studies. The present study highlights some historical cases of conjoined twins and a conjoined triplet preserved at the Morgagni Museum of Human Anatomy to show the development of medical theories in the teratological field between the 18th and early 19th century. This approach will provide insights into different study methods and ideas of some of the most famous scholars working in Padua at that time. The current article focuses on rare cases, both human and animal, that were encountered by physicians who worked in the Veneto area in the late 18th and early 19th century. Their detailed descriptions are not only of historical but also of contemporary dysmorphological value.

Women and their health care provider (HCP) often seek advice for drug safety in pregnancy at Teratology Information Services (TIS). In turn, TIS ask for details of drug exposure and pregnancy outcome. These data constitute a valuable basis for research on prenatal drug risks in many countries. Non-response to follow-up questionnaires, however, may cause biased study results. To assess the potential of non-response bias, this study based on the German Embryotox cohort compares maternal and HCP characteristics of responders and non-responders. Change in loss of follow-up rates over time is investigated using logistic regression. From 2010 until the end of 2020, 48,410 pregnant women and/or their HCP consented to participation in follow-up. Of these, 25.0 % did not return follow-up questionnaires. Loss rates were similar for patients and HCP but increased over time. Participants from semi-dense populated areas had a smaller loss rate (20.4 %) than those from rural (28.4 %) or urban areas (25.6 %). Responding women were older than non-responders, had a lower BMI, a more positive attitude towards pregnancy, a higher educational level, a lower number of previous pregnancies, smoked less, and indicated alcohol consumption more but social drugs less often. Non-response bias cannot be ruled out in studies based on observational data on drug use in pregnancy as those collected by TIS. However, differences between the complete and lost-to follow-up cohort do not suggest a particularly high or low risk profile for one of the cohorts that might substantially confound study results or even mask or mimic potential drug toxicity.

Sorcha Ní Fhlainn is a senior lecturer in film studies and American studies at Manchester Metropolitan University. She specializes in gothic studies, horror cinema, popular culture, and American studies indeed. Her work is focused in particular on vampire and monster narratives. She has published a long list of essays and several books, among which the collections Our Monster Skin: Blurring the Boundaries Between Monsters and Humanity(2010), The Worlds of Back to the Future: Critical Essays on the Films (2010), Clive Barker: Dark Imaginer (2017), and her monograph Postmodern Vampires in Film, Fiction and Popular Culture (2019).

Phenytoin is a known human teratogen with unknown etiology. Several mechanisms have been proposed including disturbances in folate metabolism, induction of embryonic hypoxia following phenytoin-induced bradycardia, free radical formation following re-oxygenation and phenytoin-induced maternal hyperglycemia. Using high frequency ultrasound, we demonstrated that phenytoin induced a dramatic decrease in the heart rate of embryos. This coincided with a moderate transient decrease in maternal heart rate and blood glucose levels. Embryonic heart rate had not fully recovered 24 h later in some embryos despite normal maternal physiological parameters. In a separate study, extent of hypoxia was measured using the marker pimonidazole. Phenytoin-exposed embryos did not demonstrate increased hypoxia compared to control embryos at 2, 4, 8 or 24 h dosing. Together our results show that phenytoin induces malformations as a result of a combination of insults: embryonic bradycardia, maternal bradycardia and maternal hyperglycemia. However, this does not appear to result in measurable embryonic hypoxia in our animal model.

Previous studies have suggested that arsenic crosses the placenta and affects the fetus development. The study under consideration aims to show comparative ameliorative effect of Moringa oleifera leaf and flower extracts against sodium arsenate induced fetus toxicity of mice. Pregnant mice (N=44) were kept in lab and divided into eleven group from (A to K) and were orally administered the doses 6 mg/kg, 12 mg/kg for sodium arsenate, 150 mg/kg and 300 mg/kg for Moringa oleifera leaf extracts (MOLE) and 150 mg/kg and 300 mg/kg for Moringa oleifera flower extracts (MOFE) comparing with control. The investigation revealed evident reduction in the fetuses weight, hind limb, fore limb, tail and snout length, crown rump and head circumferences well as malformations in tail, feet, arms, legs, skin and eyes in the negative control group (only administered with sodium arsenate). Co-administration of sodium arsenate with MOLE and MOFE ameliorate the reversed effect of sodium arsenate on the shape, length, body weight and DNA damage of fetus significantly at 95% confidence interval. However, Moringa oleifera leaf extract showed more significant results in comparison to Moringa oleifera flower extract. Hence concluded that Moringa oleifera leaf extract ameliorated the embryo toxic effects of sodium arsenate and can be used against environmental teratogens. Resumo Estudos anteriores sugeriram que o arsênio atravessa a placenta e afeta o desenvolvimento do feto. O estudo em consideração visa mostrar o efeito melhorador comparativo de extratos de folhas e flores de Moringa oleifera contra a toxicidade fetal induzida por arseniato de sódio em camundongos. Camundongos grávidas (N = 44) foram mantidos em laboratório e divididos em 11 grupos (de A a K) e foram administrados por via oral nas doses de 6 mg/kg, 12 mg/kg para arseniato de sódio, 150 mg/kg e 300 mg/kg para extratos de folhas de Moringa oleifera (MOLE) e 150 mg/kg e 300 mg/kg para extratos de flores de Moringa oleifera (MOFE) em comparação com o controle. A investigação revelou redução evidente no peso do feto, membro posterior, membro anterior, comprimento da cauda e focinho, coroa, nádega e circunferência da cabeça, bem como malformações na cauda, pés, braços, pernas, pele e olhos no grupo de controle negativo (apenas administrado com arseniato de sódio). A coadministração de arseniato de sódio com MOLE e MOFE melhora significativamente o efeito reverso do arseniato de sódio na forma, comprimento, peso corporal e dano ao DNA do feto, com intervalo de confiança de 95%. No entanto, o extrato da folha da Moringa oleifera apresentou resultados mais significativos em comparação ao extrato da flor da Moringa oleifera. Portanto, concluiu que o extrato da folha de Moringa oleifera melhorou os efeitos tóxicos do arseniato de sódio para o embrião e pode ser usado contra teratógenos ambientais.

Contains fulltext : 291894.pdf (Publisher’s version ) (Open Access) The collection of the Narrenturm in Vienna houses and maintains more than 50,000 objects including approximately 1200 teratological specimens; making it one of the biggest collections of specimens from human origin in Europe. The existence of this magnificent collection-representing an important resource for dysmorphology research, mostly awaiting contemporary diagnoses-is not widely known in the scientific community. Here, we show that the Narrenturm harbors a wealth of specimens with (exceptionally) rare congenital anomalies. These museums can be seen as physical repositories of human malformation, covering hundreds of years of dedicated collecting and preserving, thereby creating unique settings that can be used to expand our knowledge of developmental conditions that have to be preserved for future generations of scientists.

Background and purpose: Teratological cases in insects can be of different characteristic, quite often they are bifurcations, for example of antennal segments or parts of the legs. The aim of this paper is to report a remarkable case of leg duplication in Carabus violaceus L. Materials and methods: In the context of an interdisciplinary monitoring in the frame of a conservation project on the European bison (Bison bonasus (L.)) in Poland the carabid fauna (Carabidae) on areas grazed by this species was studied using pitfall traps in the Pszczyna forest, located in Silesia Province, to the south of the town Tychy. The traps were located inside a mixed fresh coniferous forest, with domination of Scots pine (Pinus sylvestris L.). Results: Among the carabids gathered a remarkable teratological female specimen of the species Carabus violaceus L. with repeated anatomical duplications on the right front leg was collected. Conclusions: The repeated incident of bifurcation suggest a genetic base of the teratology. An increased rate of teratological cases may have potential as bioindicator.

The Japan Drug Information Institute in Pregnancy (JDIIP) was established in 2005 as a project of the Ministry of Health, Labour and Welfare with the aims of providing information on drug safety to women who are worried about drug use during pregnancy and creating evidence through epidemiological studies based on counseling cases. Since being established, JDIIP has made many contributions to the wellness of mothers and children by promoting the proper use of drugs during pregnancy. However, some studies have shown that this alone is not enough to meet potential needs. From now on, it is hoped that the hub hospitals in the 47 prefectures will take the lead in promoting regional pharmaceutical cooperation and striving for equalization in this field. Pharmacists will play an important role in this effort. In particular, many women consult pharmacists during lactation because they are out of touch with their obstetricians. If the wording of the section on lactating women in the package insert is faithfully explained, breastfeeding and drug therapy become incompatible. However, in most cases, it is possible to achieve both if the benefits of breastfeeding and the amount of drug transfer into milk are taken into consideration. Counseling on drug treatment during lactation is a field where pharmacists who are skilled in reading package inserts and pharmacokinetics should play an active role. The newly established the Japan Drug Information in Pregnancy Society aims to provide a place for pharmacists who do not have many opportunities to learn about this field.

BACKGROUND: We have recently shown that alcohol and cannabis can interact prenatally, and in a recent review paper we further identified Parvalbumin-positive (PV) interneurons in the hippocampus as a potential point of convergence for these teratogens. METHODS: A 2 (EtOH, Air) x 2 (THC, Vehicle) design was used to expose pregnant Sprague-Dawley rats to either EtOH or air, in addition to either THC or the inhalant vehicle solution, from gestational days 5–20. Immunohistochemistry was performed to detect parvalbumin-positive interneurons in one male and one female pup from each litter at post-natal day (PND) 70. RESULTS: Significant between-group, and sub-region specific, effects were found in the dorsal CA1 subfield, as well as the ventral DG. In the dorsal CA1 subfield, there was an increase in the number of PV interneurons in both the EtOH and EtOH + THC groups, but only a possible decrease with THC alone. There were fewer changes in interneuron numbers overall in the DG, however, a sex difference was found, and a decrease in the number of PV interneurons in the THC exposed group was observed in the male ventral DG. There was also an increase in cell layer volume between the EtOH + THC group and control group in the DG, and an increase from the control and THC group to the EtOH group in the CA1 region. CONCLUSIONS: Prenatal alcohol and prenatal THC exposure differentially affect parvalbumin interneuron numbers in the hippocampus, indicating that both individual and combined exposure can impact the balance of excitation and inhibition in a structure critically involved in learning and memory processes.

OBJECTIVE: Prenatal exposure to the antiseizure medication (ASM) valproate is associated with an increased risk of congenital malformations, but warnings against the use of valproate in pregnancy were not issued until 2009. The objective was to study how early administrative health registers could have identified the teratogenic risk associated with valproate.METHODS: This was a population-based cohort study of individual-linked data from Danish health care and socioeconomic registers including children born in Denmark between January 1, 1997 and December 31, 2014. Information on ASM use, including valproate, in pregnancy was obtained from the Danish National Prescription Registry. Children identified with major congenital malformations from the Danish National Patient Register and the Danish Register of Causes of Death were included. Using logistic regression models, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for major congenital malformations during the first year of life in children with and without prenatal exposure to ASMs adjusted for potential confounders.RESULTS: Among the 895 507 children (males, 51.3%), 31 790 (3.6%) were diagnosed with a major congenital malformation in the first year of life. In the analyses including children born in 1997, the risk of major congenital malformations among children prenatally exposed to valproate compared with children not exposed to ASMs was increased by a fully adjusted OR (aOR) of 3.95 (95% CI = 1.65-9.47). With the addition of data from the following years, the teratogenic effect of valproate was further substantiated, as the precision of the estimate improved (1997-2014: aOR = 2.44, 95% CI = 1.80-3.30).SIGNIFICANCE: Using Danish health care data, we were able to identify a teratogenic risk associated with prenatal valproate exposure in children born in 1997, which is much earlier than prospective clinical cohorts. Health registry data represent an important tool for early identification of risk associated with drugs in pregnancy.

Coronavirus disease 2019 (Covid-19) pandemic affects all populations, including pregnant women. Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection in pregnancy needs to be a concern because of the risk of transplacental transmission to the fetus and the potential to interfere with fetal development. The objective of this study is to review the transplacental transmission of COVID-19 and the teratological aspects of the event. This article is a literature study. Based on the literature obtained, placental infection, vertical transmission, and fetal infection have been identified in some cases. However, there is still no consistent and enough scientific evidence to show that those condition causes fetal damage or causes congenital anomalies. Virus and host characteristics are thought to explain why SARS-Cov-2 infection has not shown a teratological effect. SARS-CoV-2, similar to severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) infection, does not indicate maternal-fetal transmission. The low-level expression of angiotensin-converting enzyme 2 (ACE2) and S protein priming proteases type II transmembrane serine protease (TMPRSS 2) in the placenta is also considered to be the factor that plays a role in inhibiting the vertical transmission of COVID-19. Adverse outcome of fetal death is more due to pathophysiological conditions of maternal health caused by SARS-CoV-2 infection during gestation.

To review updates regarding teratogens and give pediatric healthcare providers insight into the prevention of teratogenic exposures.Application of the principles of teratology can help to assess the potential for exposures to be teratogenic. Identification of Zika virus as a teratogen, the most recent teratogenic agent identified, allowed public health measures to be put in place to mitigate its spread. Risk management strategies for teratogenic medications have resulted in a decrease but often not elimination of prenatal exposures. The failure to include pregnant persons in clinical trials results in their being less likely to receive needed medications and vaccines in a timely manner.Pediatricians play an important role in the prevention of teratogenic exposures. Ensuring optimal management of patients with chronic illnesses that might increase their risk of birth defects during pregnancy due to the illness itself or its treatment is essential. For patients with pregnancy potential who are on teratogenic medications, ensuring effective contraception is also important. Inclusion of pregnant persons in clinical trials and research studies will be critical to advancing our knowledge of the safety of medications and other exposures during pregnancy.

Background Hydroxychloroquine is a treatment for rheumatic disease and considered safe during pregnancy. Interest in hydroxychloroquine has increased as it is being examined as a potential treatment and prophylaxis for coronavirus disease 2019. Data on the risks of specific birth defects associated with hydroxychloroquine use are sparse. Methods Using data from two case–control studies (National Birth Defects Prevention Study and Slone Epidemiology Center Birth Defects Study), we described women who reported hydroxychloroquine use in pregnancy and the presence of specific major birth defects in their offspring. Cases had at least one major birth defect and controls were live‐born healthy infants. Women self‐reported medication use information in the few months before pregnancy through delivery. Results In total, 0.06% (19/31,468) of case and 0.04% (5/11,614) of control mothers in National Birth Defects Prevention Study, and 0.04% (11/29,838) of case and 0.05% (7/12,868) of control mothers in Birth Defects Study reported hydroxychloroquine use. Hydroxychloroquine users had complicated medical histories and frequent medication use for a variety of conditions. The observed birth defects among women taking hydroxychloroquine were varied and included nine oral cleft cases; the elevated observed:expected ratios for specific oral cleft phenotypes and for oral clefts overall had 95% confidence intervals that included 1.0. Conclusion While teratogens typically produce a specific pattern of birth defects, the observed birth defects among the hydroxychloroquine‐exposed women did not present a clear pattern, suggesting no meaningful evidence for the risk of specific birth defects. The number of exposed cases is small; results should be interpreted cautiously.

Introduction Gastroschisis is a congenital malformation characterized by intestinal herniation through an abdominal wall defect. Despite its unknown pathogenesis, known risk factors include maternal smoking, alcohol use, and young maternal age. Previous work has shown that gastroschisis is associated with placental delayed villous maturation, and the goal of this study was to assess for additional associated placental pathologies that may help clarify the pathogenesis of gastroschisis. Methods We conducted a retrospective slide review of 29 placentas of neonates with gastroschisis. Additionally, we reviewed pathology reports from one control group of 30 placentas with other congenital malformations. Gross and histological data were collected based on a standardized rubric. Results Gastroschisis was associated with increased placental fetal vascular malperfusion (FVM) in 62% of cases (versus 0% of controls, p Conclusion Our study demonstrates an association between gastroschisis and FVM. While FVM could be the consequence of vascular disruption due to the ventral location of gastroschisis, it could also reflect estrogen-induced thrombosis in early pregnancy. Further research is needed to separate these possibilities and determine the cause of the placental FVM observed in gastroschisis.

Background The developing hippocampus and cerebellum, unique among brain regions, exhibit a secondary surge in neurogenesis during the third trimester of pregnancy. Ethanol (EtOH) exposure during this period is results in a loss of tissue volume and associated neurobehavioral deficits. However, mechanisms that link EtOH exposure to teratology in these regions are not well understood. We therefore analyzed transcriptomic adaptations to EtOH exposure to identify mechanistic linkages. Methods Hippocampi and cerebella were microdissected at postnatal day (P)10, from control C57BL/6J mouse pups, and pups treated with 4 g/kg of EtOH from P4 to P9. RNA was isolated and RNA-seq analysis was performed. We compared gene expression in EtOH- and vehicle-treated control neonates and performed biological pathway-overrepresentation analysis. Results While EtOH exposure resulted in the general induction of genes associated with the S-phase of mitosis in both cerebellum and hippocampus, overall there was little overlap in differentially regulated genes and associated biological pathways between these regions. In cerebellum, EtOH additionally induced gene expression associated with the G2/M-phases of the cell cycle and sonic hedgehog signaling, while in hippocampus, EtOH-induced the pathways for ribosome biogenesis and protein translation. Moreover, EtOH inhibited the transcriptomic identities associated with inhibitory interneuron subpopulations in the hippocampus, while in the cerebellum there was a more pronounced inhibition of transcripts across multiple oligodendrocyte maturation stages. Conclusions These data indicate that during the delayed neurogenic period, EtOH may stimulate the cell cycle, but it otherwise results in widely divergent molecular effects in the hippocampus and cerebellum. Moreover, these data provide evidence for region- and cell-type-specific vulnerability, which may contribute to the pathogenic effects of developmental EtOH exposure.

Purpose To study if second-generation antipsychotic (S-GA) use during the first trimester of pregnancy is associated with an increased risk of major congenital malformations (MCM). Methods A population-based birth cohort study using national register data extracted from the Drugs and Pregnancy database in Finland, years 1996–2017. The sampling frame included 1,273,987 pregnant women. We included singleton pregnancies ending in live or stillbirth or termination of pregnancy due to severe malformation. Pregnancies with exposure to known teratogens were excluded. Women were categorized into three groups: exposed to S-GAs (n = 3478), exposed to first-generation antipsychotics (F-GAs) (n = 1030), and unexposed (no purchases of S-GAs or F-GAs during pregnancy, n = 22,540). We excluded genetic conditions and compared the prevalence of MCMs in S-GA users to the two comparison groups using multiple logistic regression models. Results Use of S-GAs during early pregnancy was not associated with an increased risk of overall MCMs compared to unexposed (adjusted odds ratio, OR 0.92; 95% CI 0.72–1.19) or to F-GA users (OR 0.82; 95% CI 0.56–1.20). Of individual S-GAs, olanzapine use was associated with an increased risk of overall MCMs (OR 2.12; 95% CI 1.19–3.76), and specifically, an increased risk of musculoskeletal malformations (OR 3.71; 95% CI 1.35–10.1) when compared to unexposed, while comparisons to F-GA users did not show significant results. Conclusions Olanzapine use is associated with an increased risk of major congenital malformations and specifically, musculoskeletal malformations. Use during pregnancy should be restricted to situations where no safer alternatives exist.

Over the past 50 years, published studies have provided quantitative data on the control of epileptic seizures during pregnancy. The studies have varied in quality, and particularly in the ways in which seizure control has been assessed. However, most studies have shown that seizure occurrence rates are more likely to worsen than improve during pregnancy, though in most pregnancies the rates have been unaltered. Nearly all of the studies have involved women with antiseizure medication-treated epilepsy, but there is a little evidence that seizure control also tends to worsen in pregnancies of women with untreated epilepsy. The factors likely to contribute to the seizure worsening are (i) patient non-compliance, (ii) increased antiseizure medication clearance during pregnancy resulting in lower circulating drug concentrations relative to dose, (iii) the effects of the higher female sex hormone levels during pregnancy, oestrogens being pro-epileptogenic and progesterone anti-epileptogenic, and (iv) reluctance to use the potential teratogen valproate in women capable of pregnancy, depriving them of the most effective drug for certain types of epilepsy. Compliance can be encouraged, but at the present time only one other factor is readily correctable, i.e. the increased drug clearance. This can be compensated for by raising antiseizure medication dosage during pregnancy, guided by measurement of circulating drug concentrations. This course of action appears to reduce the chance of seizure disorder worsening during pregnancy, but so far it has not provided a complete solution to the issue.

Contains fulltext : 235748.pdf (Publisher’s version ) (Open Access) Several teratologic collections containing specimens with malformations and syndromes are maintained in a number of Dutch anatomical museums. Technically, these are not works of art or antiquities. However, many have been depicted in illustrations of such high quality that they merit discussion here. We review a selection of specimens and their artistic portrayals which find their origin in four Dutch teratological collections. These museum specimens are more than just intriguing objects for the inquisitive museum visitor. As we will substantiate, these specimens-and their artistic depictions-can be used to find and describe rarely occurring birth defects, provide etiopathogenetic information and are a source of novel diagnosis. Additionally, we briefly discuss the ethical aspects and motivations of exhibiting these specimens, as these collections have to be protected meticulously by the new generation of museum professionals, who eventually determine what kind of past our future will have. It is therefore imperative that these collections of antique specimens are treasured as their importance is easily overlooked.

Objectives Alcohol consumption causes several harmful effects on the organs, which is hugely understated. Many deformities occur in the fetus when pregnant mothers indulge in alcoholism. Alcohol is a known teratogen, hence organ formation, particularly development of parts brain critical for cognitive function may be affected. The oxidative brain damage also could contribute to reduced cognitive efficiency of brain exposed to alcohol. In this study, effect of Centella asiatica in relieving the oxidative brain damage in offspring of alcohol fed mother rats was evaluated. Methods In this study we fed alcohol (5 g/kg body weight, 30% w/v) to a group of pregnant Wistar rats during gestation period, and another group served as control. Four groups of rats (n = 6 each) were selected from the offspring of these mother rats. The groups were, control, positive (treated) control, untreated and treated from alcohol-fed mother. Their cognitive parameters were tested in water maze, shuttle box and compared. Further their oxidative status was evaluated by estimating malondialdehyde (MDA), protein carbonyl, total antioxidants and glutathione reductase (GSH) in hippocampus. Results The results suggested that there was significantly high cognitive performance in maze test and shuttle box memory retention in rats treated with C. asiatica water extract and the antioxidant levels were high in their hippocampus. Conclusions The outcome of the study suggested that C. asiatica produced beneficial effects in reversing the alcohol induced brain damage in pregnancy.

Chromium (Cr) is an element present in nature in mineral form. It has a dual effect, both as an essential micronutrient and a carcinogenic agent depending on its chemical form and concentration. It is present in various environmental matrices such as water, soil, and air, coming from natural and anthropogenic sources, and causes harmful effects on biota, ecosystems, and even human beings. This study's objective was to evaluate chromium toxicity and teratogenicity in zebrafish embryos of Danio rerio exposed to chromium through the D. rerio teratology assay ( Dar TA) test by evaluating spine malformations. To this end, the chromium toxicity curve was calculated from zebrafish embryos exposed to potassium dichromate (K 2 Cr 2 O 7 ), and the probit test was used to establish the mean lethal concentration (LC50) and three subtoxic concentrations LC 25 , LC 12.5 , and LC 6.25 to evaluate the teratogenicity. The results showed that potassium dichromate was statistically positive for the teratogenic effect at the three highest concentrations evaluated. Potassium dichromate exposure causes abnormal embryonic development and teratogenic effects, including severe heart defects in zebrafish embryos. Therefore, we conclude that potassium dichromate is toxic to the zebrafish developmental stages. The finding that potassium dichromate is teratogenic in zebrafish embryos suggests that this metal should be tested and evaluate potential risk in mammalian systems.

Background Leading Teratology Information Systems (TIS) arose in major industrial nations and are mostly in English. The prevalence of anglophone speakers in Ukraine is among the lowest in Europe. A TIS in Ukrainian (UTIS) seeks to diminish an information gap concerning teratogens. The process and results related to UTIS are applicable to formulations of other TIS in vernacular languages. Methods Implementation of a free-access UTIS and analysis of utilization patterns. UTIS provides access to articles in Ukrainian (AU) which are summaries extracted from leading international TIS and other sources. AU are revised at least tri-annually. Results UTIS provides access to over 1,100 AU accrued since 2016 to the present. The number AU views increased from nearly 30,000 (2016) to over 80,000 (2020); the number of visitors increased from 3,500 to 58,000 during the same periods. The highest percent of users per urban population (2.09, 1.77, and 1.72) was in Ternopil, Ivano-Frankivsk, and Kyiv (capital), respectively; the lowest was in Odesa (0.17). Conclusions UTIS reduced an information gap in Ukraine concerning teratogenic risk factors. The process can be implemented elsewhere relying on generally available local resources.

Potential fetal adverse effects are well-known for several antibacterial classes. The present study was performed to evaluate the potential teratogenic effect of Tilmicosin (TMS) antibiotic in Sprague Dawley rats. TMS was daily administered orally to pregnant rats at two dose levels, 250 or 500 mg/kg bw, on 6-15 days of gestation. The morphological or skeletal malformations were non-significantly different from control values. However, visceral examination revealed elevation in the percentage of intrathoracic and intracranial haemorrhages, and kidney hypoplasia (unilateral or bilateral) in fetuses from dams treated with the high dose. In addition, both dose levels produced fetuses with increased percentages of dilated brain ventricles, heart ventricles and renal pelvis. Histopathologically, both TMS doses induced pathological changes in fetal liver and kidney, in a dose-dependent manner. Liver showed hepatocyte hydropic degeneration, congestion of hepatic blood vessels, engorgement of bile canaliculi and dilatation of hepatic lymphatic vessels. Kidney revealed coagulative necrosis of renal tubules and glomerular tuft, adhesion between the parietal and visceral layers of Bowman’s capsule and the glomerular tuft became ring shape with the presence of multiple layer glomerular tufts. In conclusion, TMS antibiotic has the potential to induce teratogenic effects (mainly visceral) and pathological changes in liver and kidneys tissues of rat fetuses when administered during the organogenesis period. This result demonstrated the ability of TMS to pass the placental barrier.

Background To determine the frequency of malformations that would be identified in the limited surface examination of a newborn by the delivering nurse midwife in a resource-limited setting. Methods The limited surface examination will identify visible external anomalies, but not abnormalities inside the mouth, most heart defects, undescended testes, inguinal hernias, hip dysplasia, peripheral vascular anomalies, and some internal anomalies. The findings in a malformations surveillance program, involving 289,365 births in Boston, have been used to establish the prevalence rate of malformations that would be identified and not identified. In African countries, the number of anomalies to be identified should also be reduced by excluding polydactyly, postaxial, type B, a common minor finding, from the list of potential malformations. Results Of note, 2.05% (n = 5,941) of the 289,365 births surveyed had one or more malformations. The abnormalities that would have been missed, using surface exam alone, accounted for 0.5% of all of malformations identified and reduced the overall prevalence rate of malformations to 1.5%. In addition, excluding all infants with isolated postaxial polydactyly, type B reduced the expected prevalence rate of malformations to 1.3% in unexposed newborn infants. Conclusion A limited surface examination can detect the majority of malformations among newborn infants.

AIMS Papaverine is indicated for abdominal pain of various aetiologies. However, data on maternal and foetal safety following gestational exposure are lacking. The aim was to examine whether first trimester exposure to papaverine is associated with increased risk for major malformation and whether gestational exposure at any stage is associated with increased risk for preterm delivery, lower birthweight, small for gestational age, caesarean section (CS), lower Apgar score and perinatal death. METHODS A retrospective comparative study consisted of pregnant women treated with papaverine between February 2010 and October 2019 at a large tertiary center. The control group comprised of livebirth deliveries randomly selected from the institutional obstetric database. RESULTS The study group consisted of 498 pregnancies, which resulted in 537/544 (98.7%) live births, of whom 46/537 (8.6%) were exposed during the first trimester. The control group consisted of 498 pregnancies and 514 live births. Rate of major malformations did not differ between study group (2/46, 4.3%) and control (25/315, 4.9%, P = .67). Papaverine exposure was associated with higher rate of preterm delivery (22.3 vs. 10.3%, P

Over the last years, issues concerning diatom teratological forms and environmental stress have received growing interest within the scientific community. Publications on this topic dated back to 1890 and were summarized in a review published in 2009 by the journalHydrobiologia, accounting for high citation rates (i.e. 117 citations Scopus and 232 citations Google Scholar, October 2020). This wide interest stimulates the authors to further unravel teratological forms significance in the light of the most recent publications (2010–2020). Diatom teratological forms are one of the best individual-level biomarkers since they provide a rapid response to several environmental stressors, including new emerging pollutants. The mechanisms involved in teratological valve likely involve both cytoskeleton and silicon metabolic pathway impairments. However, teratologies do not seem to weaken the reproduction capacity and viability of the affected individuals. We recognized eight types of teratologies as involving different parts of the valve, depending on genus. In order to summarize the information obtained by several years of research, we suggest a four-step procedure aimed at providing a theoretical pathway that researchers should follow to better explain results obtained in next-future studies and representing a starting point for the development of an environmental index based on teratological forms.

BACKGROUNDThe function of the gestational sac (GS) and the placenta in the closely related processes of embryogenesis and teratogenicity in the first trimester has been minimally described. The prevailing assumption is that direct teratogenic effects are mediated by the critical extraembryonic organ, the placenta, which either blocks or transfers exposures to the foetus. Placental transfer is a dominant mechanism, but there are other paradigms by which the placenta can mediate teratogenic effects. Knowledge of these paradigms and first trimester human developmental biology can be useful to the epidemiologist in the conduct of biomarker-based studies of both maternal and child health.OBJECTIVE AND RATIONALEOur aim is to provide a causal framework for modelling the teratogenic effects of first trimester exposures on child health outcomes mediated by the GS and placenta using biomarker data collected in the first trimester. We initially present first trimester human developmental biology for the sake of informing and strengthening epidemiologic approaches. We then propose analytic approaches of modelling placental mechanisms by way of causal diagrams using classical non-embryolethal teratogens (diethylstilboestrol [DES], folic acid deficiency and cytomegalovirus [CMV]) as illustrative examples. We extend this framework to two chronic exposures of particular current interest, phthalates and maternal adiposity.SEARCH METHODSInformation on teratogens was identified by a non-systematic, narrative review. For each teratogen, we included papers that answered the five following questions: (i) why were these exposures declared teratogens? (ii) is there a consensus on biologic mechanism? (iii) is there reported evidence of a placental mechanism? (iv) can we construct a theoretical model of a placental mechanism? and (v) can this knowledge inform future work on measurement and modelling of placental-foetal teratogenesis? We prioritized literature specific to human development, the organogenesis window in the first trimester and non-embryolethal mechanisms.OUTCOMESAs a result of our review of the literature on five exposures considered harmful in the first trimester, we developed four analytic strategies to address first trimester placental mechanisms in birth cohort studies: placental transfer and direct effects on the foetus (DES and maternal adiposity), indirect effects through targeted placental molecular pathways (DES and phthalates), pre-placental effects through disruptions in embryonic and extraembryonic tissue layer differentiation (folic acid deficiency), and multi-step mechanisms that involve maternal, placental and foetal immune function and inflammation (DES and CMV).WIDER IMPLICATIONSThe significance of this review is to offer a causal approach to classify the large number of potentially harmful exposures in pregnancy when the exposure occurs in the first trimester. Our review will facilitate future research by advancing knowledge of the first trimester mechanisms necessary for researchers to effectively associate environmental exposures with child health outcomes.

The impact of certain medication exposures in utero can be observed in the physical development of the fetus (e.g. patterns of congenital malformations or dysmorphic features) or in the form of growth disruption. Developmental trajectories within the fetal brain can also be susceptible to alteration and can manifest as lifelong neurodevelopmental impairments. Despite growing recognition of its importance as an outcome, a lack of coherence within the investigation of the neurodevelopmental outcomes remains. Important methodological clarity could be gained through reviewing published data regarding neurodevelopmental outcomes within the context of confirmed structural teratogens. This scoping review will use systematic searches to identify neurodevelopmental outcome data for medications demonstrated to alter the physical development of the fetus (i.e. structural malformations or growth disruption). Searches will be conducted in MEDLINE, EMBASE, and the specialized database Reprotox. Identified abstracts will be doubly reviewed against the eligibility criteria and data extracted. A narrative review will be undertaken, reporting on the key neurodevelopmental areas frequently altered, methodological features of completed studies (e.g. study designs, child characteristics, dose relationships, etc) and, importantly, the relationship between the structural alterations associated with the exposure and the observed neurodevelopmental outcomes.

Alvarezsauroidea (Tetanurae) are nonavian theropod dinosaurs whose forelimb evolution is characterised by the overdevelopment of digit I, at the expense of the other two digits, complemented by a drastic forelimb shortening in derived species (Parvicursorinae). These variations are recognised as evolutionary developmental anomalies. Evolutionary teratology hence leads to a double diagnosis with (1) macrodactyly of digit I and microdactyly of digits II and III, plus (2) anterior micromelia. The teratological macrodactyly/microdactyly coupling evolved first. Developmental mechanisms disturbing limb proportion are thought to be convergent with those of other Tetanurae (Tyrannosauridae, Carcharodontosauridae). As for the manual anomalies, both are specific to Alvarezsauroidea (macrodactyly/microdactyly) and inherited (digit loss/reduction). While considering the frame-shift theory, posterior digits develop before the most anterior ones. There would therefore be a decrease in the area devoted to digits II (condensation 3) and III (condensation 4), in connection with the Shh signalling pathway, interacting with other molecular players such as the GLI3 protein and the Hox system. Developmental independence of digit I (condensation 2) would contribute to generating a particular morphology. Macrodactyly would be linked to a variation in Hoxd-13, impacting Gli3 activity, and increasing cell proliferation. The loss/reduction of digital ray/phalanges (digits II and III), would be associated with Shh activity, a mechanism inherited from the theropodan ancestry. The macrodactyly/microdactyly coupling, and then anterior micromelia, fundamentally changed the forelimb mechanical function, compared to the 'classical' grasping structure of basal representatives and other theropods. The distal ossification of the macrodactylian digit has been identified as physiological, implying the use of the structure. However, the debate on a particular 'adaptive' use is pointless as the ecology of an organism is interactively complex, being both at the scale of the individual and dependent on circumstances. Other anatomical features also allow for compensation and different predation (cursorial hindlimbs).

Genetic and environmental factors have been observed to influence risks for birth defects, though few studies have investigated gene-environment interactions. Our aim was to examine the interaction terms of gene variants in biotransformation enzyme pathways and air pollution exposures in relation to risk of several structural birth defects. We evaluated the role of ambient air pollutant exposure (nitrogen dioxide [NO2 ], nitrogen oxide, carbon monoxide, particulate matter

Objective Prenatal exposure to the antiepileptic drug (AED) valproic acid (VPA) is associated with an increased risk of impaired postnatal neurodevelopment, including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). We aimed to evaluate the influence of sex and drug dosage on the association between prenatal VPA exposure and postnatal behavioral outcomes. Methods The Australian Pregnancy Register of AEDs was interrogated to identify children aged 4-11 years prenatally exposed to AEDs. Parents reported on their child's behavior using the Autism Spectrum Quotient-Children's Version and the National Institute for Children's Health Quality Vanderbilt Assessment Scale for ADHD. General linear mixed-effects models were used to investigate the relationship between clinicodemographic variables and psychometric scores. Results A total of 121 children were studied: 54 prenatally exposed to VPA (28 males, 26 females; mean dose ± SD: 644 ± 310 mg/day) and 67 exposed to other AEDs. There was a main effect of sex showing higher ASD scores in males compared to females (p = .006). An interaction between sex and VPA exposure revealed that males had higher ASD symptoms among children exposed to AEDs other than VPA (p = .01); however, this typical sex dynamic was not evident in VPA-exposed children. There was no evidence of any dose-response relationship between VPA exposure and ASD symptoms. Males had higher ADHD scores compared to females, but there was no evidence for a link between ADHD symptoms and VPA exposure. Significance Prenatal VPA exposure seems to negate the usual male sex-related predominance in the incidence of ASD. These initial findings deepen the concept of VPA as a "behavioral teratogen" by indicating that its effect might be influenced by sex, with females appearing particularly sensitive to the effects of VPA. No association between VPA doses and adverse postnatal behavioral outcomes was detected, possibly related to the low VPA doses used in this study.

The purpose of the research was to evaluate the teratogenic effect caused by theprovision of Arabica coffee solution with variations of 0.36 ml, 0.72 ml and 1.08 ml withpositive control of caffeine at a dose of 300 mg / kg bw to rats during organogenesis. Themeasurement parameters in this study are the appearance of reproduction, externalmalformations and scalal malformations. The results in this study found that theadministration of Arabica coffee solution with a volume of 1.08 ml and caffeine 300 mg /kg bb caused an abnormality in the reproductive appearance of weight loss and body length,whereas for extrenal malformation and scalal malforation no abnormalities were found ineach administration of the solution Arabica coffee and caffeine.

The objective of the study was to evaluate the rate of major congenital anomalies after first trimester exposure to ondansetron for nausea and vomiting of pregnancy (NVP). The design is a prospective, comparative, observational cohort study, performed at the Israeli Teratology Information Service between 2010 and 2014. Follow-up was obtained for 195 ondansetron-exposed, 110 metoclopramide-exposed, and 778 pregnancies with non-teratogenic exposure (NTE). The overall rate of major anomalies did not significantly differ between the groups [4/200 = 2.0 % (ondansetron), 1/109 = 0.9 % (metoclopramide), and 13/731 = 1.8 % (NTE)]. All the anomalies in both the ondansetron and metoclopramide groups, and 6/13 anomalies in the NTE group, were cardiac septal defects most of which spontaneously resolved. Both ondansetron (adjHR = 0.29, 95 % CI 0.10-0.80) and metoclopramide (adjHR = 0.27, 95 % CI 0.08-0.86) were associated with lower miscarriage rate compared to NTE. Based on the present study, ondansetron during pregnancy is not associated with an increased risk for overall major anomalies, nor for clinically important cardiac defects. It may be a reasonable alternative for women with severe NVP who do not respond to first line medications.

Ipomoea carnea is a toxic plant found in Brazil and other tropical countries. The plant contains the alkaloids calystegines and swainsonine, which inhibit key cellular enzymes and cause systematic cell death. It is known that swainsonine is excreted in the amniotic fluid of dams exposed to the plant. Thus, the aim of this study was to verify whether the toxic effect of I. carnea on fetuses is due to exclusively the passage of the active principle of the plant through the placenta, or if the placentotoxic effect of swainsonine could collaborate in the adverse effects observed in the fetus. The teratogenic effects of exposure to the toxic principles of I. carnea were evaluated not only using the conventional protocol but also at later stages in the postnatal developmental period. Females were treated, from gestation day (GD) 6 until GD19, with 0.0, 1.0, 3.0 or 7.0 g/kg body weight of I. carnea dry leaves. The plant did not induce changes in reproductive performance or biochemical profile of the dams. Dams that received the highest dose of I. carnea showed cytoplasmic vacuolization in the liver, kidney and placental tissue. I. carnea promoted different lectin binding patterns in different areas of placental tissue. No fetal skeletal or visceral malformations was observed. The postnatal evaluation revealed a lower litter weight and a lower pup body weight one day after birth in the group that received the highest dose of I. carnea. Physical milestones were unaffected by the treatments. Female pups from all experimental groups exhibited a delay in achieving a negative geotaxis response. The results show that the toxic principle of I. carnea produces injury in utero in mothers and fetuses, but these deleterious effects were better demonstrated using postnatal evaluation.

We have studied the embryo-fetal toxicity of mephedrone in mice during organogenesis period on gestation day (GD) 6–15 in mice during organogenesis period intraperitoneally. Our observation showed ...

Objectives The severe acute respiratory syndrome coronavirus 2 (COVID-19) outbreak in Italy, especially in Lombardy and Bergamo city, represented probably nowadays one of the first major clusters of COVID-19 in the world. The aim of this report is to describe the activity of Bergamo Teratology Information Service (TIS) in supporting the public and health-care personnel in case of drug prescriptions in suspected/confirmed COVID-19 pregnant and lactating patients during COVID-19 outbreak in Italy. Methods All Bergamo TIS requests concerning COVID-19 pregnant and lactating women have been retrospectively evaluated from 1 March to 15 April 2020. Type of medications, drug’s safety profile and compatibility with pregnancy and lactation are reported. Results Our service received information calls concerning 48 (9 pregnant, 35 lactating) patients. Among pregnant and lactating women, the requests of information were related to 16 and 60 drugs prescriptions respectively. More than half concerned drugs prescriptions during the first and second trimester (13/16) and during the first six months of lactation (37/60). Hydroxychloroquine and azithromycin were the most involved. Conclusions Hydroxychloroquine and azithromycin at dosages used for COVID-19 may be considered compatible and reasonably safe either in pregnancy and lactation. Antivirals may be considered acceptable in pregnancy. During lactation lopinavir and ritonavir probably exhibit some supportive data from literature that darunavir and cobicistat do not. Tocilizumab may be considered for COVID-19 treatment because no increased malformation rate were observed until now. However caution may be advised because human data are limited and the potential risk of embryo-fetal toxicity cannot be excluded.

The impact of pesticides on the environment and human health is a serious matter of concern. The present study focusses on the teratogenic effect of pesticide chlorpyrifos (CPF) and glyphosate (GLY) on the pregnant rats and their offspring during gestation and lactation period. The female rats were exposed to these pesticides (CPF and GLY) throughout their pregnancy at a dose of 10 mg/kg. The biochemical markers and lipid profile of pesticides exposed pregnant rats were analyzed. The maternal and reproductive outcome was also assessed followed by rat pups morphometric analysis. A significant alteration in the blood glucose level, triglycerides, total cholesterol, SGOT, and SGPT levels were observed in pesticide exposed groups. The body weight, crown-rump length, eye length, eye width, hind limb, and forelimb size of rat neonates were significantly found to be lower in the pesticide exposed group when compared with the control animals. Morphological abnormalities like microcephaly, microtia, micromelia, dysmorphogenesis, distorted axis abdominal, and brain hemorrhages were observed in pesticide exposed rat neonates. Skeletal observations of the CPF exposed group show disruptive malformations, wavy ribs, and curved spinal cord. Intraventricular and spinal cord hemorrhages were observed in 21 days old rat pups in GLY treated group. Findings of the present study indicate that exposure to pesticides during the gestation period causes the morphological abnormalities in rat fetuses by altering the mechanisms involved in growth and development. Thus, on the basis of observed results, we concluded the teratogenic effects of CPF and GLY in rats.

Teratology is the science that deals with the causes and patterns of deformities, abnormalities and defects in the physical development of animals. Teratological occurrences can be due to genetic o...

PurposeTraditional Malaysian vegetables, also known as ulam, are believed to have healing properties among the local community. Ulam is commonly reported to have high antioxidant content which makes it a popular food. The purpose of this paper is to determine the teratogenic potential of eight ulam, using zebrafish model. The tested ulam were Cosmos caudatus, Gynura procumbens, Labisia pumila var. alata, Phaleria macrocarpa, Polygonum minus, Piper sarmentosum, Premna foetida and Sauropus androgynous.Design/methodology/approachMethanol extract of ulam was prepared using the maceration method. Various concentrations of extracts were tested against fish embryo short-term toxicity test. The lethal concentration (LC50) and teratogenic effect of the ulam were determined.FindingsAmong all tested species, L. pumila, P. foetida and S. androgynous showed 100% lethal effect towards zebrafish embryos at concentrations of 10 µg/mL, 1,000 µg/mL and 100 µg/mL, respectively. The three ulam have exhibited teratogenic effect on zebrafish embryos after 72 h post-fertilization. L. pumila had induced yolk sac edema at 1.0 µg/mL for normalized measurement of 108.3 ± 2.0% (which is higher than negative control, p P. foetida had induced pericardial edema at 100 µg/mL for normalized measurement of 124.0 ± 4.6% (which is higher than negative control, p S. androgynus induced curve trunk at 30 µg/mL for the presence of 70.9 ± 4.2%.Originality/valueThe teratogenic effect of L. pumila, P. foetida and S. androgynous suggests the possible disruption in the embryogenesis in zebrafish, namely Notch, vascular endothelial growth factor (VEGF) and retinoic acid pathways. The results of ulam gave possible implications and insights on the cancer pathways involved, which could be a useful target for cancer research. This is the first report on teratogenicity evaluation of Malaysian ulam showing relationship to cancer pathways by using zebrafish embryo model.

The early identification of teratogens in humans and animals is mandatory for drug discovery and development. Zebrafish has emerged as an alternative model to traditional preclinical models for predicting teratogenicity and other potential chemical-induced toxicity hazards. To prove its predictivity, we exposed zebrafish embryos from 0 to 96 h post fertilization to a battery of 31 compounds classified as teratogens or non-teratogens in mammals. The teratogenicity score was based on the measurement of 16 phenotypical parameters, namely heart edema, pigmentation, body length, eye size, yolk size, yolk sac edema, otic vesicle defects, otoliths defects, body axis defects, developmental delay, tail bending, scoliosis, lateral fins absence, hatching ratio, lower jaw malformations and tissue necrosis. Among the 31 compounds, 20 were detected as teratogens and 11 as non-teratogens, resulting in 94.44 % sensitivity, 90.91 % specificity and 87.10 % accuracy compared to rodents. These percentages decreased slightly when referred to humans, with 87.50 % sensitivity, 81.82 % specificity and 74.19 % accuracy, but allowed an increase in the prediction levels reported by rodents for the same compounds. Positive compounds showed a high correlation among teratogenic parameters, pointing out at general developmental delay as major cause to explain the physiological/morphological malformations. A more detailed analysis based on deviations from main trends revealed potential specific modes of action for some compounds such as retinoic acid, DEAB, ochratoxin A, haloperidol, warfarin, valproic acid, acetaminophen, dasatinib, imatinib, dexamethasone, 6-aminonicotinamide and bisphenol A. The high degree of predictivity and the possibility of applying mechanistic approaches makes zebrafish a powerful model for screening teratogenicity.

Objective Thyroid disorders including hyperthyroidism are common during pregnancy. Untreated hyperthyroidism can result in adverse outcomes for pregnancy. Methods Iodine, propylthiouracil (PTU), carbimazole (CMZ), and methimazole (MMI) are common medications for hyperthyroidism treatment. The literature regarding antithyroid medication use in pregnancy and breastfeeding is reviewed. Results Animal studies for PTU have suggested congenital anomalies while animal studies for MMI have only indicated adverse outcomes at higher doses than used in humans. Epidemiological studies have noted an increased risk of congenital anomalies for PTU less often than CMZ or MMI but the epidemiological evidence remains mixed. A pattern of anomalies has been described for CMZ and MMI, from both case and epidemiological studies, including choanal atresia, aplasia cutis congenita, and other facial, heart, gastrointestinal, and skin anomalies. Closer examination of cases indicates that a few cases of the anomalies have occurred without exposure to CMZ or MMI and outside of the proposed critical period. PTU has a small risk of hepatotoxicity which rarely results in liver transplantation and death. Some authors have suggested that PTU be prescribed in early pregnancy and switched to MMI in late pregnancy. Untreated hyperthyroidism, from either a lack of medications or switching medications during the first trimester, may also increase the chance of congenital anomalies. Multiple case studies and larger epidemiological studies have failed to provide clear, consistent outcomes for the use of PTU, CMZ, and MMI in pregnancy. MMI and PTU both enter the breastmilk in small amounts. Conclusion Additional research is needed to assist in the medical management and exposure counseling of pregnant and breastfeeding women with hyperthyroidism.

The generative function of female rats upon intragastric administration of tablets of gestobutanoil at doses of 0.25 and 2.5 mg/kg (calculated doses corresponding to the therapeutic dose and ten times higher) was studied. Gestobutanoil was administered two weeks before pregnancy, which corresponded to 2 – 3 estrous cycles. Gestobutanoil at a dose of 0.25 mg/kg exhibited progestogen activity. The duration of estrus, the fertility index, and the numbers of pregnancy corpus lutea and live fetuses increased in female rats. Administration of gestobutanoil at a dose of 2.5 mg/kg produced a contraceptive effect that manifested as a prolonged estrous cycle and a reduction of fertility and numbers of corpus lutea and fetuses. Gestobutanoil at both doses did not produce a teratogenic effect and did not affect the vitality of F1 offspring (survival, body-weight dynamics, sensory-motor behavior development).

Valproic acid (VPA) is a branched short-chain fatty acid primarily used in epilepsy, but is also used in bipolar disorder, migraine, and psychotic disorders. Despite its wide range of use, it is a teratogen resulting in various congenital abnormalities. Although a large number of scientific studies evidenced the teratogenic effects, there are limited data on embryonic exposure to VPA at specific or different stages of early embryogenesis. Based on this, the present study was planned to investigate the embryonic exposure to VPA at specific and different hours post fertilization (hpf) in zebrafish embryonic model. In first set of experiments, embryos from spawning groups of adult zebrafish were exposed to different molar concentrations of VPA at 2.5 hpf, and in the second set of experiments, embryos were exposed to VPA 100 μM at 24 hpf, 36 hpf, 48 hpf, 72 hpf, and 96 hpf. The parameters examined were hatching rate, mortality, morphology, body length, pericardial sac size, heartrate, anatomical changes in heart, skeletal and notochord till 120 hpf. It was observed that the embryos exposed to VPA at 2.5 hpf suffered from cardiac abnormalities including heart malformation, bradycardia, circulatory failure, and pericardial sac enlargement which was more apparent in embryos exposed to 100 μM VPA. In the second set of experiments, embryos exposed to VPA 100 μM at 24 hpf and 36 hpf suffered from heart malformations, but there was no incidence of cardiac malformation in embryos exposed to VPA at 48 hpf, 72 hpf, and 96 hpf. From the results, it was evident that exposure to VPA at early developmental stage of embryogenesis produced congenital cardiac abnormalities. Since VPA is a selective HDAC inhibitor, histone acetylation with aberrant gene expression during cardiogenesis might be the underlying cause of cardiac malformation.

Absztrakt: Fogamzás alkalmával a gének által meghatározottan egy új egyed jön létre, amelynek struktúráját és tulajdonságait (működését, a részletek együttműködését és annak időbeliségét, valamint erősségét (expresszivitását) gének feletti (epigenetikus) szabályozás rendezi, mely program formájában rögzül. Ez a program folyamatosan alakul és alakítható, miközben hibák történhetnek, melyek a program tartós elemeivé válnak, illetve megzavarják a fiziológiás program működését. Vannak az élet folyamán különösen érzékeny periódusok (mint a perinatalis (praenatalis – fetalis-neonatalis, korai postnatalis időszak), amikor az epigenetikus hatások (imprinting) fiziológiásan rögzülnek, és ezek közé sorolható a pubertás időszaka is. Ugyanakkor az átprogramozás nincs időkorlátok közé szorítva, hanem a sejtek fejlődési állapotától függ, így differenciálódó sejtekben (sejtcsoportokban) bármely életkorban megtörténhet. Az átprogramozott sejtek ezután az új programnak megfelelően funkcionálnak, az élet végéig. Ez az adott életfunkció normálistól való eltéréséhez, tartós meggyengüléséhez vagy éppen megerősödéséhez vezethet, de akár (a normális szabályozásból kiszakadva) daganatképződés alapja is lehet. A programozásban és átprogramozásban alapvető szerepe van az endokrin rendszernek (hormonoknak), így a környezetünkben megjelenő hormonszerű molekulák (endokrin diszruptorok) képesek életreszólóan megzavarni a programot, ami a hibás hormonális imprinting, illetve a DOHaD (Developmental Origin of Health and Disease) teóriájában nyeri el magyarázatát. Az átalakult (hibás) program az utódgenerációkra átöröklődik. Míg a perinatalisan fellépő, de csak később megnyilvánuló zavar már többé-kevésbé ismertnek és elismertnek tűnik (a hibás hormonális imprinting és a DOHaD teóriája), a későbbi életkorokban (elsősorban pubertáskorban), de bármely életkorban differenciálódó sejtekben történő átprogramozódás kevésbé ismert, pedig hasonló problémákat okozhat. A megváltozott program az utódgenerációkra öröklődik, és az utódban már ennek további átprogramozódása történik meg. Mindezt figyelembe véve az endokrin diszruptorok provokálta – felnőttkorban fellépő – betegségek szaporodása várható. Orv Hetil. 2020; 161(25): 1028–1034.

The recent introduction of evolutionary teratology has led to the diagnosis of certain anatomical features as developmental anomalies integrated into phylogenies. This approach is part of a broader theoretical restructuring. The application of evolutionary teratology to the forelimbs of non-avian theropod dinosaurs has focused on the drastic forelimbs shortening and manual anomalies of some representatives, both in Ceratosauria and Tetanurae. Evolutionary teratological diagnosis can also be made during post-natal growth, differentiating juvenile and adult stages. The methods of evolutionary teratology and its scales of discussion highlight the need to redefine certain Darwinian notions, leading to consider evo-devo as a connection between disciplines. This aspect is unconsciously reflected by calls for various inclusions within a modern synthesis evolving towards an evolutionary extended synthesis. However, this step cannot be an end in itself, as the paradigm of synthesis is carrying Darwinian functional defects. Pluralism is an alternative way to overcome these imbalances, implying cultural restructurings.

Background Craniofacial anomalies are among the most frequent birth defects worldwide, and are thought to be caused by gene‐environment interactions. Genetically manipulated zebrafish simulate human diseases and provide great advantages for investigating the etiology and pathology of craniofacial anomalies. Although substantial advances have been made in understanding genetic factors causing craniofacial disorders, limited information about the etiology by which environmental factors, such as teratogens, induce craniofacial anomalies is available in zebrafish. Results Zebrafish embryos displayed craniofacial malformations after teratogen treatments. Further observations revealed characteristic disruption of chondrocyte number, shape and stacking. These findings suggested aberrant development of cranial neural crest (CNC) cells, which was confirmed by gene expression analysis of the CNC. Notably, these observations suggested conserved etiological pathways between zebrafish and mammals including human. Furthermore, several of these chemicals caused malformations of the eyes, otic vesicle, and/or heart, representing a phenocopy of neurocristopathy, and these chemicals altered the expression levels of the responsible genes. Conclusions Our results demonstrate that chemical‐induced craniofacial malformation is caused by aberrant development of neural crest. This study indicates that zebrafish provide a platform for investigating contributions of environmental factors as causative agents of craniofacial anomalies and neurocristopathy.

BACKGROUND Given the potential hazards of teratogenic medicines, to a fetus exposed in utero, monitoring their use around pregnancy is imperative. AIM To measure utilisation of teratogenic medicines (Therapeutic Goods Administration's category D or X) in women who gave birth in New South Wales, Australia, during pregnancy and the 24 months prior. MATERIALS AND METHODS We used linked population-based datasets including dispensing and perinatal data for all deliveries in NSW between 2005 and 2012. We included pregnancies among concessional beneficiaries only, with complete ascertainment of dispensing claims. Pre-pregnancy and during-pregnancy periods were based on birth dates and gestational age. We determined prevalence of exposure using percent of pregnancies in which women had at least one dispensed teratogenic medicine in three-month time periods. RESULTS The study included 191 588 pregnancies (145 419 women). Prevalence of exposure to D/X medicines anytime during pregnancy was 2.0% (