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Correlated responses in female reproductive performance were evaluated following short-term selection within full-sib families for increased 8-week body weight in two replicates of four lines of mice: two ovine metallothionein-ovine growth hormone (oMt1a-oGH) transgene-carrier lines, one from a high-growth background (TM) and one from a control background (TC), and two non-transgenic lines, one from each of these genetic backgrounds (NM and NC, respectively). A fifth line (CC), not containing the transgene, served as a randomly selected control. The initial frequency of the oMt1a-oGH transgene construct in the TM and TC lines was 0.5. The frequency of transgenic females sampled at generations 7 and 8 of selection was 84.0% and 6.1% in the TC and TM lines, respectively. No significant female infertility differences were detected between transgene-carrier and non-transgenic lines or between transgenic and non-transgenic mice within carrier lines, whereas high-growth background lines had a higher infertility than control background lines (P < 0.05). Correlated responses in the TC transgene-carrier line were suggestive of reduced reproductive performance as indicated by increased post-implantation mortality (P < 0.05), number of dead fetuses plus implants (P < 0.05), and loss of fetuses from day 16 to parturition (P < 0.001). For the first two traits, the negative correlated responses were accounted for by the reduced performance of transgenic compared with non-transgenic females. Embryos carrying the transgene may also have a lower viability. In contrast, the NC non-transgenic line did not exhibit reduced reproductive performance for these traits. The low frequency of the transgene in the high-growth background TM line was associated with reduced fitness and a lower additive effect for 8-week body weight compared with the control background TC line.

The purpose of this study was to evaluate selection in lines of transgenic mice. Two replicates of lines that either carried or did not carry the sheep metallothionein-1a sheep growth hormone transgene (oMt1a-oGH) were established. The host lines had been previously selected for rapid growth or selected randomly. Within-litter selection for increased 8-wk body weight was carried out for 13 generations. The frequency of oMt1a-oGH was monitored in all generations in the transgenic lines, but no genotypic information regarding the transgene was used as an aid to selection. The oMt1a-oGH was activated from weaning, at 3 wk, until 8 wk of age by adding ZnSO4 to the drinking water. Zinc stimulation of the transgene was not done during mating, gestation, or lactation. Data on body weights and weight gains were analyzed with a conventional mixed model and with an animal model. Genetic progress was achieved in all lines subjected to directional selection. In the control background, response to selection for 8-wk body weight was larger in the nontransgenic lines than in the transgenic lines, whereas no difference was found in the selected background. The frequency of the transgene was increased from the initial .5 to .62 in the randomly selected background but decreased to .04 in lines from a selected background. The REML estimates of variance components and genetic gain estimates varied greatly between the two methods. In general, there was better agreement between the realized heritability estimates and the heritability estimates obtained from the conventional mixed model analysis than between realized heritability estimates and results obtained using the animal model. Favorable correlated responses were obtained for 3- and 6-wk body weights and on 3- to 6- and 6- to 8-wk weight gains. Correlated responses to selection were larger in the selected than in the nonselected background but were not affected by the presence of the transgene. Results suggest that constructs similar to the oMt1a-oGH, which allow tight regulation, may be successfully incorporated into commercial livestock and should have larger effects in populations that have not been subject to selection.

Attachment of the sheep metallothionein la promoter to the sheep growth hormone gene (oMT1a-oGH) has resulted in a closely regulated transgene in mice that can respond to elevated levels of zinc ions provided in the drinking water. The objective of this study was to explore the effects of zinc ion concentration on postweaning growth, fat content, organ size, and female reproduction. At weaning (3 weeks of age), hemizygous oMT1a-oGH mice were assigned randomly to receive 0, 12.5, 25, 37.5, or 50 mM ZnSO4 in distilled drinking water for 5 weeks. Males were killed at 8 weeks and selected organs and fat pads were weighed. Females received tap water from 8 to 10 weeks and then were mated to unrelated non-transgenic fertile males to obtain ovulation rate and embryo survival. Mortality rate was increased (P < 0.05) at 37.5 mM (15.2%) and 50 mM (33.3%) ZnSO4 compared with lower levels. Postweaning growth was highest at 12.5 mM ZnSO4 followed by 25 and 37.5 mM, respectively. At 50 mM ZnSO4, 8 week-old males were 20% smaller than males not receiving a supplement while females did not differ from females not receiving a supplement. Epididymal (EFP) and subcutaneous (SFP) fat pad weights of males decreased linearly (P < 0.01) with increased dosage of ZnSO4, while on a percentage of body weight basis, EFP and SFP decreased quadratically (P < 0.01). Males receiving 12.5 mM ZnSO4 had their EFP and SFP as a percentage of body weight reduced (P< 0.01) to 54.1% and 65.9% of controls (0 mM), respectively. As a percentage of body weight, liver spleen and kidney weights increased with doses of 12.5, 25 and 37.5 mM ZnSO4 compared with no supplemental zinc, while testis weight as a percentage of body weight was reduced (P < 0.05); percentage heart weight was only reduced at 12.5 mM (P < 0.05). No significant differences in female fertility were associated with ZnSO4 treatment. Females receiving ZnSO4 supplement had higher ovulation rates than those that received no supplement, but there were no differences (P > 0.05) in ovulation rates among the zinc levels. A decrease (P < 0.05) in pre- and post-implantation embryo survival was detected at 37.5 mM ZnSO4. These results indicate that zinc dosage affects phenotypic expression of the oMT1a-regulated oGH transgenic mice, and the dose responses are trait-dependent.

Objective: To determine the frequency of acanthosis nigricans (AN) in a group of hirsute, hyperandrogenic women and to determine the body site most frequently affected., Design: Cross-sectional observational study., Setting: University teaching hospital., Patients, Participants: Reproductive age, nonhypertensive, nondiabetic women referred for evaluation of hirsutism, documented to have hyperandrogenism, without medications known to influence lipid, carbohydrate, or hormonal metabolism., Interventions: None., Main Outcome Measures: Presence of AN. Insulin resistance was assessed by measuring fasting glucose, fasting insulin, and nadir glucose after a 0.1 U/kg i.v. insulin bolus in both obese and nonobese, hirsute, hyperandrogenic women., Results: Twenty-four of 43 women were found to have AN. Although AN was identified at several body sites including the axilla (n = 14), on the nape of the neck (n = 13), below the breasts (n = 7), and on the inner thigh (n = 7), it was always present on the vulva in women who displayed one or more lesions. Acanthosis nigricans was found only in the obese, hirsute, hyperandrogenic women. These women were the most insulin resistant., Conclusions: Acanthosis nigricans and insulin resistance are found frequently in obese, hirsute, hyperandrogenic women. The vulva is the most likely place to find this marker.

Objective: The purpose of our study was to further understand interrelationships between insulin, androgens, obesity, and apolipoprotein metabolism., Study Design: In this University cross-sectional observational study for hypothesis generation, 53 women with hirsutism-hyperandrogenism were ternately divided according to body mass index into the following groups: 22 to 28 (n = 17), 29 to 36 (n = 19), 37 to 61 (n = 17), and 16 controls. Mean hormone and clinical parameters were compared by using the Student t test, analysis of variance, and Pearson correlation., Results: Dehydroepiandrosterone sulfate correlated negatively with fasting insulin (r = 0.4, p < 0.05) and reached significance in those most obese. Unbound testosterone concentrations were 24.7, 38.9, and 31.9 ng/dl, respectively. Dehydroepiandrosterone sulfate concentrations were 2.8, 2.3, and 2.3 micrograms/dl, respectively; their ratios were 13.4, 18.6, and 20.4, respectively, even though mean fasting insulin concentrations (reflecting insulin resistance) were 13.0, 20.4, and 42.6 microU/ml, respectively. Although more atherogenic apolipoprotein profiles and higher fasting insulin concentrations were found with greater body weight, lipid-insulin interrelationships may reflect dehydroepiandrosterone sulfate interaction., Conclusions: We hypothesize that dehydroepiandrosterone sulfate dampens the effect of insulin resistance, which in turn is reflected in apolipoprotein profiles in women with hirsutism/hyperandrogenism.

Objective: We attempted to evaluate apolipoprotein lipid levels in hirsute hyperandrogenic women and to clarify the influence of insulin resistance versus endogenous sex steroids on these profiles., Study Design: Forty-seven women seen for evaluation of hirsutism in the Reproductive Endocrine Clinic were contrasted with 15 normal women. Thirty-one patients were treated with the gonadotropin-releasing hormone analog, leuprolide acetate, 7.5 mg intramuscularly monthly for 3 months. Insulin resistance was assessed before and after GnRH analog administration. Mean concentrations were compared with the Student t test and analysis of variance., Results: Hirsute women were heavier and had higher systolic and diastolic blood pressures, more menstrual irregularities (all p less than 0.01), and higher waist/hip ratios (p less than 0.05). They had higher triglyceride, very-low-density lipoprotein C-III levels and lower high-density lipoprotein cholesterol concentrations (all p less than 0.01). They had lower apolipoprotein A-I/A-II ratios (p less than 0.01). After administration of GnRH analog, androgen and estrogens were suppressed and insulin resistance was unaltered. Insulin correlated with apolipoprotein lipid abnormalities., Conclusion: Lipid and apolipoprotein abnormalities in these hirsute women seem to be associated more with insulin resistance than with endogenous androgens or estrogens.