Influences of pre- and postnatal testosterone treatment on defeminization of sexual receptivity in pigs

Sexual receptivity was evaluated in female and male pigs that had experienced varying periods of exposure to testosterone pre- and postnatally. For prenatal exposure, pregnant sows were treated with testosterone propionate (TP) from Day 29-35 or Day 39-45 of gestation at a dosage that caused virilization of the external genitalia of their female offspring. Eighty-three percent of the females that received TP prenatally had regular estrous cycles, but reached puberty later than control females. Only 26% of the females that received TP both pre- and postnatally (4-6 mo of age) were observed in estrus by 10 mo of age. After ovariectomy and acute treatment with estradiol benzoate (EB), the proportion of females that showed the immobilization response (receptivity) was similar for all groups of females independent of pre- or postnatal TP treatment. Females treated prenatally from Day 39-45 showed the immobilization response for fewer days after treatment with a high dosage of EB than did controls. On the basis of these observations, we conclude that receptivity in female pigs is not affected greatly by testosterone treatment at the stages of development that were investigated. Males castrated at birth and treated with a single injection of EB after 9.5 mo showed the immobilization response. In contrast, few males castrated at 8 mo or castrated at birth and treated with TP from 3 to 6 mo showed the immobilization response after EB treatment. These observations provide direct evidence for a postnatal component of testosterone-dependent defeminization of receptivity in male pigs.     

Period of maximal susceptibility to behavioral modification by testosterone in the golden hamster

Male hamsters castrated on the day of birth (Day 1) and female hamsters were treated with the free form of testosterone (100 μg/day) on Days 1 and 2, 3 and 4, 5 and 6, 7 and 8, or 9 and 10 postnatally. Following androgen treatment in adulthood, animals treated on Days 1 and 2 or 3 and 4 showed significantly higher mounting and intromission frequencies than animals treated later in life. Sexual receptivity measures following ovarian hormone treatment showed no differences among the male groups, whereas females treated on Days 1 and 2 or 3 and 4 were significantly lower in sexual receptivity measures than females in other treatment groups. Histology of the adult ovaries indicated no modification of normal function in any treatment group. In a subsequent experiment, Day 1 castrated male and intact female hamsters were treated with the free form of testosterone on Days 1–5 (40 or 100 μg/day), 6–10 (40 or 100 μg/day), or Days 1–10 (50 μg/day). Masculine behavior measures were significantly higher in males treated Days 1–10 than in other groups. Among the females, masculine behavior was highest in those treated Days 1–5 postnatally. Sexual receptivity in both males and females was significantly depressed by testosterone treatment Days 1–10 postnatally. Ovarian histology also revealed alterations in gonadal function in females treated Days 1–5 and 1–10 postnatally. Compared with previously published findings, these data suggest that testosterone can be as effective in inducing behavioral masculinization and defeminization as testosterone propionate, provided that treatment extends over a prolonged period during early postnatal development.     

Some Long-Lasting Neurochemical Efafects of Prenatal or Early Postnatal Exposure to Diazepam

Changes in the uptake of various neurotransmitters were measured in the frontal cortex and hippocampus of male and female rats that were exposed to diazepam through the placenta or through the mother's milk during the prenatal or early postnatal period of rapid brain development. Earlier studies from our laboratory showed that early diazepam exposure has long-lasting behavioral consequences. The present results show that prenatally diazepam-exposed rat pups show significant reduction in choline uptake in the frontal cortex at 10 days of age. At 60 days of age, both pre- and postnatally exposed males, but not females, show significant differences from controls in terms of choline uptake, whereas postnatally exposed females whose behavior was shown previously to be profoundly affected by the diazepam exposure showed significant increase in gamma-aminobutyric acid (GABA) uptake in the hippocampus and reduction of 5-hydroxytryptamine (5HT) uptake in the cortex at 60 days of age.     

Maternal LPS Exposure during Pregnancy Impairs Testicular Development,Steroidogenesis and Spermatogenesis in Male Offspring

Lipopolysaccharide (LPS) is associated with adverse developmental outcomes including embryonic resorption, fetal death, congenital teratogenesis and fetal growth retardation. Here, we explored the effects of maternal LPS exposure during pregnancy on testicular development, steroidogenesis and spermatogenesis in male offspring. The pregnant mice were intraperitoneally injected with LPS (50 µg/kg) daily from gestational day (GD) 13 to GD 17. At fetal period, a significant decrease in body weight and abnormal Leydig cell aggregations were observed in males whose mothers were exposed to LPS during pregnancy. At postnatal day (PND) 26, anogenital distance (AGD), a sensitive index of altered androgen action, was markedly reduced in male pups whose mothers were exposed to LPS daily from GD13 to GD 17. At PND35, the weight of testes, prostates and seminal vesicles, and serum testosterone (T) level were significantly decreased in LPS-treated male pups. At adulthood, the number of sperm was significantly decreased in male offspring whose mothers were exposed to LPS on GD 13–17. Maternal LPS exposure during gestation obviously diminished the percent of seminiferous tubules in stages I–VI, increased the percent of seminiferous tubules in stages IX–XII, and caused massive sloughing of germ cells in seminiferous tubules in mouse testes. Moreover, maternal LPS exposure significantly reduced serum T level in male mice whose mothers were exposed to LPS challenge during pregnancy. Taken together, these results suggest that maternal LPS exposure during pregnancy disrupts T production. The decreased T synthesis might be associated with LPS-induced impairments for spermatogenesis in male offspring.     

Risk of Childhood Overweight after Exposure to Tobacco Smoking in Prenatal and Early Postnatal Life

Objective

To investigate the association between exposure to mothers smoking during prenatal and early postnatal life and risk of overweight at age 7 years, while taking birth weight into account.

Methods

From the Danish National Birth Cohort a total of 32,747 families were identified with available information on maternal smoking status in child''s pre- and postnatal life and child''s birth weight, and weight and height at age 7 years. Outcome was overweight according to the International Obesity Task Force gender and age specific body mass index. Smoking exposure was categorized into four groups: no exposure (n = 25,076); exposure only during pregnancy (n = 3,343); exposure only postnatally (n = 140); and exposure during pregnancy and postnatally (n = 4,188). Risk of overweight according to smoking status as well as dose-response relationships were estimated by crude and adjusted odds ratios using logistic regression models.

Results

Exposure to smoking only during pregnancy, or both during pregnancy and postnatally were both significantly associated with overweight at 7 years of age (OR: 1.31, 95% CI: 1.15–1.48, and OR: 1.76, 95% CI: 1.58–1.97, respectively). Analyses excluding children with low birth weight (<2,500 gram) revealed similar results. A significant prenatal dose-response relationship was found. Per one additional cigarette smoked per day an increase in risk of overweight was observed (OR: 1.02, 95% CI: 1.01–1.03). When adjusting for quantity of smoking during pregnancy, prolonged exposure after birth further increased the risk of later overweight in the children (OR 1.28, 95% CI:1.09–1.50) compared with exposure only in the prenatal period.

Conclusions

Mother''s perinatal smoking increased child''s OR of overweight at age 7 years irrespective of birth weight, and with higher OR if exposed both during pregnancy and in early postnatal life. Clear dose-response relationships were observed, which emphasizes the need for prevention of any tobacco exposure of infants.     

Postnatal Environmental Tobacco Smoke Exposure Related to Behavioral Problems in Children

ObjectiveThe purpose of this study was to examine the association between pre and post environmental tobacco smoke (ETS) exposure and behavioral problems in schoolchildren.MethodsIn the cross-sectional 6 cities Study conducted in France, 5221 primary school children were investigated. Pre- and postnatal exposure to secondhand tobacco smoke at home was assessed using a parent questionnaire. Child’s behavioral outcomes (emotional symptoms and conduct problems) were evaluated by the Strengths and Difficulties Questionnaire (SDQ) completed by the parents.ResultsETS exposure during the postnatal period and during both pre- and postnatal periods was associated with behavioral problems in children. Abnormal emotional symptoms (internalizing problems) were related to ETS exposure in children who were exposed during the pre- and postnatal periods with an OR of 1.72 (95% Confidence Interval (CI)= 1.36-2.17), whereas the OR was estimated to be 1.38 (95% CI= 1.12-1.69) in the case of postnatal exposure only. Abnormal conduct problems (externalizing problems) were related to ETS exposure in children who were exposed during the pre- and postnatal periods with an OR of 1.94 (95% CI= 1.51-2.50), whereas the OR was estimated to be 1.47 (95% CI=1.17-1.84) in the case of postnatal exposure only. Effect estimates were adjusted for gender, study center, ethnic origin, child age, low parental education, current physician diagnosed asthma, siblings, preterm birth and single parenthood.ConclusionPostnatal ETS exposure, alone or in association with prenatal exposure, increases the risk of behavioral problems in school-age children.     

Exogenous androgen during development alters adult partner preference and mating behavior in gonadally intact male rats

In the rat, neonatal administration of testosterone propionate to a castrated male causes masculinization of behavior. However, if an intact male is treated neonatally with testosterone (hyper-androgen condition), male sexual behavior in adulthood is disrupted. There is a possibility that the hyper-androgen treatment is suppressing male sexual behavior by altering the male's partner preference and thereby reducing his motivation to approach the female. If so, this would suggest that exposure to supra-physiological levels of androgen during development may result in the development of male-oriented partner preference in the male. To test this idea, male rats were treated either postnatally or prenatally with testosterone, and partner preference and sexual behavior were examined in adulthood. The principal finding of this study was that increased levels of testosterone during early postnatal life, but not prenatal, decreased male sexual behavior and increased the amount of time a male spent with a stimulus male, without affecting the amount of time spent with a stimulus female during partner preference tests. Thus, the reduction in male sexual behavior produced by early exposure to high levels of testosterone is not likely due to a reduction in the male's motivation to approach a receptive female.     

Sexual differentiation in quail: critical period and hormonal specificity

There is a discrepancy between results showing that male quail are demasculinized by exogenous estrogens only if the treatment is given before Day 12 of egg incubation and results showing that ovariectomy of females after hatching still affects their sexual differentiation which leads to the conclusion that female demasculinization by ovarian estrogens is a continuing process extending into posthatching life. The first experiment was performed to test different models which have been proposed to reconcile these apparently contradictory results. Male and female quail were treated with 0, 5, or 25 micrograms of estradiol benzoate (EB) on either Day 9 or Day 14 of embryonic life. Birds were castrated at the age of 4 days to avoid the confounding effects of postnatal gonadal hormones and were treated as adults with testosterone (T). Whereas EB-treatment demasculizined sexual behavior and cloacal gland growth of males when administered on Day 9, it was without effect on Day 14. This result confirms the presence of a "critical period" for sexual differentiation of behavior in embryonic life. However, the time course of sexual differentiation and the sensitivity to the demasculinizing actions of estrogens were not the same for different behavioral and morphological characteristics. Some dependent variables such as plasma levels of luteinizing hormone and crowing were still affected by the EB treatment on Day 14. These results show that the whole process of demasculinization is not retricted to the "critical period" ending on Day 12 of incubation. A second experiment was performed to determine if 5 beta-dihydrotestosterone (5 beta-DHT), a metabolite of testosterone, also exerts demasculinizing effects during embryonic life. A large dose of 5 beta-DHT (2 mg/egg) had no effects on behavior and morphology in males if administered on Day 9 of egg incubation. This suggests that 5 beta-DHT, which is a steroid devoid of behavioral effects in the adult bird, is also an inactive compound as far as sexual differentiation of the quail is concerned. The high 5 beta-reductase activity which was previously identified in the hypothalamus of the embryonic quail thus probably plays a protective role. By transforming testosterone into inactive nonaromatizable androgens, it prevents male embryos from being demasculinized by their endogenous testosterone acting through aromatization.     

Paradoxical effects of maternal stress on fetal steroids and postnatal reproductive traits in female mice from different intrauterine positions

We examined effects of maternal stress on prenatal serum concentrations of testosterone and estradiol and on postnatal reproductive traits in female mice from different intrauterine positions. On Day 18 of fetal life, control females positioned in utero between two male fetuses (2M females) had higher concentrations of testosterone and lower concentrations of estradiol in serum than control female fetuses located between two females (0M females). Control females positioned between a male and a female fetus (1M females) had intermediate levels of both hormones. Prior intrauterine position in control females accounted for differences in genital morphology (length of the anogenital separation) at birth and length of estrous cycles during adulthood. Maternal stress eliminated these postnatal differences due to prior intrauterine position: all 0M, 1M, and 2M female offspring of stressed mothers exhibited postnatal traits that were indistinguishable from those of control 2M females. Maternal stress resulted in an increase of over 1 ng/ml in serum testosterone in all female fetuses; the magnitude of the increase was similar for 0M, 1M, and 2M females. There was no effect of maternal stress on serum concentrations of estradiol in 0M and 2M female fetuses. Maternal stress resulted in a dramatic change in the postnatal traits of 0M females, whereas 2M females showed no change. Since the effect of maternal stress on sex steroids was similar among fetuses from different intrauterine positions but postnatal response to maternal stress varied by intrauterine position, other components of the endocrine system may mediate effects of maternal stress on these postnatal characteristics.     

Effects of prenatal exposure to low doses of diethylstilbestrol, o,p'DDT, and methoxychlor on postnatal growth and neurobehavioral development in male and female mice

We examined effects of a wide range of doses of three man-made estrogenic chemicals during fetal life on neurobehavioral changes during early postnatal life in mice. Pregnant mice were fed a 4-log range of o,p'DDT, methoxychlor (MXC), and the drug diethystilbestrol (DES) from gestation days 11 to 17. Offspring were examined for changes in postnatal growth and the development of neuromuscular reflexes. Fetal exposure to the estrogenic chemicals altered the number of live pups per litter, the sex ratio of the litters, the anogenital distance of male and female offspring at birth (a bioassay for fetal androgen action), and the body weight of offspring at birth and during the first 5 days of postnatal life. In most cases, however, the dose-response relationships were complex (non-monotonic), with effects at the highest dose examined being opposite to effects seen at lower doses. The two markers of neurobehavioral development, righting and cliff avoidance reflexes, were not sensitive indicators of prenatal estrogen exposure. Only maternal exposure to the lowest MXC dose produced an increase in reactivity in righting and cliff avoidance tests in offspring.     

In utero contiguity to males does not influence morphology, behavioral sensitivity to testosterone, or hypothalamic androgen binding in CF-1 female mice.

Physiological and behavioral systems presumably influenced by prenatal exposure to testosterone (T) were compared in CF-1 female mice from known uterine positions. Anogenital distance did not differ among females that developed in utero between two females (0M), adjacent to one male (1M), or between two males (2M) at birth, at weaning on Day 21, or on Day 60 postpartum. The age of vaginal opening and mean estrous cycle length also were similar among the groups. When ovariectomized and implanted with a T-containing silastic capsule, the mean number of days of treatment required to activate male-like aggressive behavior also did not differ among the three positional classifications. Finally, androgen binding in combined hypothalamic-preoptic-septal cytosol was assessed after 8 days of T treatment, and no systematic variation in [3H]DHT binding related to uterine position was found. These results indicate that contiguity to male fetuses did not induce variation among CF-1 females in morphological, behavioral, or biochemical systems thought to be influenced by prenatal exposure to T.     

Postnatal treatment of rats with adrenergic receptor agonists or antagonists influences differentiation of sexual behavior

The aim of the study was to investigate the possible role of the adrenergic system in development and differentiation of neural centers controlling sexual behavior in adulthood. For this purpose normal and androgenized female rats were treated with the alpha 1-receptor antagonist prazosin, the alpha 2-receptor agonist clonidine, or the alpha 2-receptor antagonist yohimbine-HCl throughout the first week of life. In adulthood all animals were ovariectomized and, after appropriate hormone-priming, they were tested for the capacity to display female and male sexual behavior patterns. Alteration of adrenergic transmission during the critical postnatal period for sexual differentiation of neural centers resulted in significant changes in the capacity to express female lordosis behavior in adulthood. In nonandrogenized animals clonidine significantly reduced the capacity for lordosis behavior. In androgenized animals clonidine had the opposite effect; it attenuated the inhibitory effect of testosterone propionate (TP) on differentiation of lordosis behavior. Prazosin, which was without effect in nonandrogenized animals, also attenuated the inhibitory effect of TP on differentiation of lordosis behavior. Yohimbine was without effect in androgenized and nonandrogenized animals. There was no influence of any of the adrenergic drugs on differentiation of male sexual behavior. In conclusion, differentiation of lordosis behavior seems to be mediated or modulated via adrenergic transmission. The defeminizing effect of testosterone postnatally on the differentiation of lordosis behavior seems to be expressed via alpha 1-adrenergic transmission, and diminished adrenergic activity during the postnatal period seems to protect the developing brain against this effect of testosterone.     

Investigation of the role of postnatal testosterone in the expression of sex differences in behavior in infant rhesus macaques (Macaca mulatta)

In several primate species, males have been shown to exhibit a surge in circulating testosterone during the early postnatal period. This surge has been postulated to play a role in the development of sex differences in behavior. In this study, the role of postnatal testosterone in infant behavioral development was investigated in socially living rhesus macaques. Seven male infants were treated with a GnRH agonist, avorelin, from the first week of life onwards. Ten female infants were exposed to testosterone by implantation of capsules containing testosterone. The behavioral development of these and control infants was recorded from birth to 6 months of age. The sexually dimorphic patterns of play and mounting were not affected by manipulation of postnatal testosterone in either male or female infants. Similarly, most mother-infant interactions were not affected by the hormonal manipulation of infants. Mothers of testosterone-treated females were found to take more responsibility for moving into and out of arm's reach of their infants than mothers of some other groups of infants; however, this measure did not normally differ between mothers of male and female infants. Manipulation of the postnatal testosterone surge does significantly affect penile growth and development, but does not affect the expression of infant sex differences in behavior nor greatly affect the development of the mother-infant relationship in rhesus macaques.     

Effects of perinatal alcohol on sexual differentiation and open-field behavior in rats

Prenatal alcohol treatment prolonged the gestation period by 1 day in 5 out of 11 mothers and decreased the anogenital distance of pups of both sexes measured at birth. There were no effects on body weights of the pups at birth, total number of pups per litter, or sex ratio. The postnatally alcohol-treated males (pups nursed by alcohol-drinking mothers) had a significantly earlier preputial separation than animals treated with alcohol prenatally only or controls. There were no differences among the groups on the parameters of adult masculine sexual behavior, plasma testosterone, weights of sex accessory glands, or open-field behavior. Animals treated perinatally with alcohol showed a significant inhibition of penile reflexes. Repeated testing, however, abolished this effect.     

Differences in Production of Adrenal Steroid Hormones in Pubertal Rats Exposed to Low Doses of the Endocrine Disruptor DDT during Prenatal and Postnatal Development

Production of adrenal steroid hormones in pubertal male Wistar rats exposed to low doses of DDT during both prenatal and postnatal and only postnatal development has been investigated. Rats exposed to the disruptor prenatally and postnatally, and only postnatally were characterized by opposite changes in production of mineralocorticoids, glucocorticoids, male and female sex hormones. The study revealed that daily exposure to low doses of DDT enhanced conversion of progesterone to 17-OH-progesterone and did not exert selective antiandrogenic or proestrogenic action typical for the effect of toxic and subtoxic doses. In rats, exposed to DDT during their prenatal and postnatal development, impaired morphogenesis of the adrenal cortex and circulatory disorders in zona glomerulosa contributed to reduced aldosterone and sex steroid hormones production.     

Pre- and postnatal development studies of lasofoxifene, a selective estrogen receptor modulator (SERM), in Sprague-Dawley rats

BACKGROUND: Lasofoxifene is a nonsteroidal selective estrogen receptor modulator (SERM) developed for the treatment of postmenopausal osteoporosis. The purpose of these studies was to evaluate the effects of lasofoxifene on the postnatal development, behavior, and reproductive performance of offspring of female rats given lasofoxifene during organogenesis and lactation. METHODS: Two range-finding studies were conducted to determine the effects of lasofoxifene at doses from 0.01-10 mg/kg on parturition and lactation in pregnant rats and on the early postnatal development of the offspring, and to optimize the dosing regimen. Maternal milk and plasma were sampled for concentrations of lasofoxifene on Lactation Days 4, 7, and 14. In the pre- and postnatal development study, lasofoxifene was administered to pregnant and lactating rats by oral gavage at dose levels of 0.01, 0.03, and 0.1 mg/kg on Gestation Days 6-17 and Lactation Days 1-20. Maternal body weight and food consumption were measured throughout pregnancy, and body weight was measured throughout lactation. Parturition was monitored closely. The F1 offspring were measured for viability, body weight, anogenital distance, the appearance of postnatal developmental indices and reflex behaviors, sensory function, in an age-appropriate functional observational battery, motor activity, auditory startle, passive avoidance, and the Cincinnati Water Maze. The F1 generation was assessed for reproductive function, and the F2 offspring were measured for body weight and viability throughout the lactation period. RESULTS: In the range-finding studies, indications of maternal toxicity included decreased body weight and food consumption, increased length of gestation, prolonged parturition, dystocia, and increased offspring mortality at birth. Concentrations of lasofoxifene in maternal plasma were similar to those in milk, increased with increasing dose, and remained consistent over a 10-day period. In the pre- and postnatal development study, maternal body weights and food consumption were decreased in all treated groups during gestation. Length of gestation was increased, parturition was prolonged, and dystocia was noted in the dams in the 0.1 mg/kg group. There was increased pup mortality in the F1 litters in the 0.1 mg/kg group and all treated groups had decreased offspring body weights beginning at 1 week of age, continuing into the postweaning period and, for the F1 males, into adulthood. Female F1 offspring in the 0.03 and 0.1 mg/kg groups had increased body weights as adults. There were delays in the age of appearance of preputial separation in the males in the 0.1 mg/kg group and vaginal opening in the females in all treated groups. Body temperature was decreased by <0.5 degrees C after weaning for male and female offspring in the 0.1 mg/kg group. The sensory, behavioral, and functional measures, including the tests of learning and memory, were unaffected by treatment. Mating success was lower for the F1 animals in the 0.1 mg/kg group, but there were no effects on the reproductive parameters. Mating, reproduction, and maternal behavior of the F1 animals in the 0.01 and 0.03 mg/kg groups and the survival and body weights of the F2 offspring in all treated groups through Postnatal Day 21 were unaffected by treatment. CONCLUSION: The maternal findings in this study were related to the pharmacologic activity of lasofoxifene. Inhibition of growth of the F1 offspring after perinatal exposure to lasofoxifene was observed, but there were no significant effects on the sensory, behavioral, or functional measures, including learning and memory. There were no effects on the F2 generation. The findings are consistent with those reported for at least one other SERM. The findings of this study do not suggest increased risk for the primary indication of use in postmenopausal women.     

Effects of genistein in the maternal diet on reproductive development and spatial learning in male rats

Endocrine disruptors, chemicals that disturb the actions of endogenous hormones, have been implicated in birth defects associated with hormone-dependent development. Phytoestrogens are a class of endocrine disruptors found in plants. In the current study we examined the effects of exposure at various perinatal time periods to genistein, a soy phytoestrogen, on reproductive development and learning in male rats. Dams were fed genistein-containing (5 mg/kg feed) food during both gestation and lactation, during gestation only, during lactation only, or during neither period. Measures of reproductive development and body mass were taken in the male offspring during postnatal development, and learning and memory performance was assessed in adulthood. Genistein exposure via the maternal diet decreased body mass in the male offspring of dams fed genistein during both gestation and lactation, during lactation only, but not during gestation only. Genistein decreased anogenital distance when exposure was during both gestation and lactation, but there was no effect when exposure was limited to one of these time periods. Similarly, spatial learning in the Morris water maze was impaired in male rats exposed to genistein during both gestation and lactation, but not in rats exposed during only one of these time periods. There was no effect of genistein on cued or contextual fear conditioning. In summary, the data indicate that exposure to genistein through the maternal diet significantly impacts growth in male offspring if exposure is during lactation. The effects of genistein on reproductive development and spatial learning required exposure throughout the pre- and postnatal periods.     

External genitalia abnormalities in male rats exposed in utero to finasteride, a 5 alpha-reductase inhibitor

A series of studies was conducted to determine the developmental toxicity of the 5 alpha-reductase inhibitor finasteride (MK-0906) in rats. This compound was administered orally once daily to pregnant rats during various extended treatment periods during gestation. F1 offspring were evaluated on Day 20 of gestation as well as postnatally through mating to produce an F2 generation. MK-0906 treatment induced dosage-related incidences of hypospadias (penischisis) in male offspring with a threshold dosage level near 0.1 mg/kg/day and a 100% effect level of 100 mg/kg/day (with dosing through Day 20 of gestation). MK-0906 also caused decreased anogenital distance in male offspring. The dosage response for this effect (ranging from a 4.2% decrease at 0.003 mg/kg/day to a 38% decrease at 100 mg/kg/day) was more shallow than that for hypospadias. The decreases in anogenital distance were at least partially reversible postnatally with essentially complete recovery at dosages up to 0.1 mg/kg/day. There was also a dosage-related, temporary induction of nipples in F1 males. All of these effects were apparent following treatment on Days 6 through 17 of gestation but were more pronounced when dosing extended to Day 20 of gestation. Slight maternal toxicity consisting of minor decreases in body weight gain occurred only at dosages of 3 mg/kg/day and higher, indicating the selective nature of the developmental toxicity. The 5 alpha-reductase enzyme located in the rat fetal genital tubercle was studied in vitro and compared to that in the adult ventral prostate. The values for Km, Vmax, and IC50 for inhibition by MK-0906 were similar in the two tissues, suggesting that the enzymatic proteins in the genital tubercle and ventral prostate may be similar.     

Thyroid hormone levels in rats exposed to alcohol during development

Maternal ingestion of alcohol appears to cause a pattern of congenital anomalies with a reduction of pre- and postnatal growth in the offspring. In order to study the possible implication of thyroid function in the effects of pre- and/or postnatal exposure to alcohol, we have studied serum thyroxine (T4) and triiodothyronine (T3) levels in rats from alcohol-fed mothers during the postnatal period (0-50 days). Blood alcohol levels of ethanol-treated pregnant rats were approximately equal to 20-25 mM and their serum T4 levels were decreased, compared with the pair-fed controls, at 15 and 21 days of gestation. No significant changes were observed in T3 levels. Prenatal alcohol exposure was associated with a decrease in both T4 and T3 levels in pups at birth. Although T4 levels continued reduced in the 40-50 days of the postnatal period, no clear effects were observed on T3 levels during this time. Moreover, the more marked alterations were obtained when the offspring were postnatally and pre + postnatally exposed to alcohol. Significant decreases were found in both T4 and T3 levels following postnatal exposure, except at the 20-25th day when a marked but transient increase in T4 levels was observed. These results indicate that alcohol exposure disturbs the hypothalamo-pituitary-thyroid axis, as measured by T3 and T4 hormone levels, mainly when the rats are exposed during the postnatal period.     

Differential effects of prenatal testosterone timing and duration on phenotypic and behavioral masculinization and defeminization of female sheep

The process of sexual differentiation leaves genetically female individuals at risk of being masculinized by exogenous androgens. Previous research with sheep indicates that exposure to excess testosterone from Gestational Day (GD) 30 to GD 90 of the 147-day gestation masculinizes and defeminizes behavior as well as genitalia. Lower doses and shorter durations produce animals with varying degrees of genital virilization and alterations of the hypothalamic-pituitary-gonadal axis, but to our knowledge, the effects on complex behavior and its prediction by the amount of external virilization have not been explored. Previous research in rodents has suggested that sexual differentiation of the central nervous system and the external genitalia can be dissociated. Therefore, we hypothesized that the extent of virilization of external genitalia would not be predictive of the lack of female-typical, or the presence of male-typical, mating behavior. To test this hypothesis, we compared control females, females exposed to exogenous testosterone from GD 30 to GD 90 (T60 females) that have virilized genitalia, and females exposed to testosterone from GD 60 to GD 90 (T30 females) that have female-typical genitalia. Both natural behavioral estrus in the flock and hormonally controlled behavioral tests were used to explore reproductive behavior. The T60 and T30 females exhibited more masculinized reproductive behavior than the controls; however, the T30 females also exhibited feminine behavior. Neither testosterone-treated group was receptive or was mounted at rates comparable to those of controls. These data illustrate that variation in the timing or duration of exposure to prenatal testosterone during a critical period for masculinization can have variable effects on defeminization and that the effects of testosterone on genitalia are not entirely predictive of behavior.