Characterization of the estrous cycle in Octodon degus

We characterized the reproductive cycle of Octodon degus to determine whether reproductive maturation is spontaneous in juveniles and if ovarian cyclicity and luteal function are spontaneous in adults. Laboratory-reared prepubertal and adult females were monitored for vaginal patency and increased wheel-running. Sexual receptivity was assessed by pairing adult females with a male 1) continuously, 2) at the time of vaginal patency, or 3) following estradiol treatment. Blood samples were assayed for estradiol and progesterone concentrations on Days 1, 4, 8, and 16 relative to vaginal opening. Ovarian tissues were collected 6 and 16 days after behavioral estrus and 6 days after copulation for histology. In juveniles, the onset of cyclic vaginal patency and increased wheel-running activity was spontaneous, occurred in the absence of proximal male cues, and appeared at regular intervals (17.5 ± 1.4 days). In adults, vaginal patency and increased wheel-running occurred cyclically (21.2 ± 0.6 days) in the absence of proximal male cues, and these traits predicted the time of sexual receptivity. Corpora lutea develop spontaneously and are maintained for 12-14 days. The ovaries had well-developed corpora lutea 6 days after mating and 6 days after estrus without mating. Progesterone concentrations were highest in the second half of the cycle when corpora lutea were present and estradiol concentrations peaked on the day of estrus. Thus, female degus appear to exhibit a spontaneous reproductive cycle consistent with other Hystricognathi rodents. Octodon degus is a novel model with which to examine the mechanisms underlying different reproductive cycles.     

Perinatal Steroid Treatments Alter Alloparental and Affiliative Behavior in Prairie Voles

This experiment was designed to examine the hypothesis that perinatal manipulation of gonadal or adrenal steroids can alter the subsequent expression of juvenile parental (alloparenting) and affiliative behavior in prairie voles (Microtus ochrogaster). Corticosterone (PRECORT), testosterone (PRE-TP), or oil injections (PRESES) were given on Prenatal Days 12–20 or on Postnatal Days 1–6 (CORT6, TP6, or SES6, respectively). Alloparenting was reduced significantly in females in the CORT6 group and in males in the TP6 group. Sibling affiliative preferences were increased significantly in PRE-TP females and stranger preferences were increased in TP6 and CORT6 females. The results suggest timing is a critical factor determining whether hormones have a facilitative or inhibitory effect on alloparental and affiliative behavior in prairie voles. In this species, corticosterone and testosterone have similar organizational effects on affiliative behavior in females. Alloparental behavior is inhibited by postnatal corticosterone administration in females and by postnatal testosterone administration in males, whereas prenatal steroid administration had no significant effect on alloparenting in either gender.     

Neonatal immune challenge alters reproductive development in the female rat

This article is part of a Special Issue "Neuroendocrine-Immune Axis in Health and Disease." Neonatal lipopolysaccharide (LPS) exposure alters neuroendocrine, immune and behavioural responses in adult rats. Recent findings indicate that neonatal LPS treatment may have a more pronounced effect on the mating behaviours of females compared to males. The current study further explored the impact of neonatal inflammation on reproductive development in the female rat. Wistar rats were administered LPS (0.05mg/kg, i.p.) or saline (equivolume) on postnatal days (PNDs) 3 and 5. The immediate effect of treatment was assessed on plasma corticosterone and tyrosine hydroxylase (TH) phosphorylation in the adrenal medulla. Weight gain and vaginal opening were recorded, and oestrous cyclicity was monitored post-puberty and in late adulthood. Blood and ovaries were collected throughout development to assess HPA and HPG hormones and to examine ovarian morphology. Reproductive success in the first (F1) generation and reproductive development in the second (F2) generation were also assessed. Neonatal LPS exposure resulted in increased TH phosphorylation in the neonatal adrenals. LPS treatment increased the corticosterone concentrations of females as juveniles, adolescents and adults, and reduced FSH in adolescence. Increased catch-up growth was evident in LPS-treated females, prompting earlier onset of puberty. Diminished follicular reserve was observed in neonatally LPS-treated females along with the advanced reproductive senescence. While fertility rates were not compromised, higher mortality and morbidity were observed in litters born to LPS-treated mothers. Female offspring of LPS-treated mothers displayed increased corticosterone on PND 14, increased catch-up growth and delayed emergence of the first oestrous cycle. No differences in any of the parameters assessed were observed in F2 males. These data suggest that neonatal immunological challenge has a profound impact on the female reproductive development, via the alteration of metabolic and neuroendocrine factors which regulate sexual maturation. Evidence of altered development in the female, but not male offspring of LPS-treated dams suggests increased susceptibility of females to the deleterious effects of neonatal immunological stress and its possible transferability to a subsequent generation.     

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.     

Conception, embryonic development and corpus luteum function in beef cattle open for two consecutive breeding seasons

High-fertility (control cows) and low-fertility (cows and heifers not pregnant after two consecutive breeding seasons — twice-open) cyclic bovine females were treated with a single injection of 1000 IU of human chrionic gonadotropin (HCG) or 100 μg of gonadotropin releasing hormone (GnRH) to enhance and/or hasten corpus luteum formation and progesterone secretion, and improve conception rate in the low-fertility females. Hormone treatments were administered to 38 parous control cows, 34 twice-open parous cows, and 27 twice-open nonparous heifers immediately after natural mating by a fertile bull. Blood samples were collected on Days 3, 6, 9, 12, and 18 after mating for determination of systemic progesterone concentrations. Pregnancy rate at necrospy approximately 33 days after mating (range 31–37) was higher in control cows (73.0%) than in twice-open cows (48.4%; P<0.05) or twice-open heifers (34.6%; P<0.01). Pregnancy rate was not affected by the HCG or GnRH treatment. The HCG treatment increased plasma progesterone concentrations in twice-open heifers but not in control or twice-open cows. Progesterone was unaffected by the GnRH treatment. Systemic progesterone concentrations were higher in control than in twice-open females but did not differ between pregnant and nonpregnant females of Days 3, 6, 9 and 12 after mating. Enhanced gonadotropin stimulation at estrus by injection of either HCG or GnRH did not increase pregnancy rate or systemic progesterone concentrations (except in HCG-treated twice-open heifers) in low- or high-fertility females. Lower pregnancy rates in twice-open females were not associated directly with the lower systemic progesterone concentrations.     

Reproductive success,postpartum maternal behavior,and masculine sexual behavior of neonatally androgenized female hamsters

Sex differences in maternal behavior induced by pup stimulation (sensitization) have been reported for rats and hamsters and may be affected by the presence or absence of perinatal androgen treatment. Postpartum maternal behavior and litter survival in golden hamsters treated with testosterone propionate (TP) as neonates were studied. A high dose of TP (300 μg) eliminated feminine reproductive capacity when given on Day 2 or 4 postpartum and had no discernible effect on Day 12. Treatment on Days 6, 8, or 10 resulted in treatment day-dependent deficiencies in reproductive success which fell short of sterility in most females. These deficiencies included low birth weight, weight gain, and higher litter losses than controls. However, the maternal behavior of TP dams, as measured by retrieval and crouching, appeared to be normal. The disparity between delivery and successful rearing of normal-weight young may include uterine incompetence, lactation deficiency, and hypercannibalism. Behavioral masculinization was a more sensitive index of neonatal androgen action than any aspect of defeminization, but the two phenomena were dissociated in individuals.     

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.     

Age at puberty and first litter size in early and late paired rats

The rate of sexual maturation among female Sprague-Dawley rats was measured in a variety of intraspecific social environments. It was found that females of this strain differ from at least one other strain of laboratory rat in that neither age at vaginal perforation nor age at first estrus was affected in Sprague-Dawley females by the presence or absence of male, regardless of his age or breeding history. Sizes of first litter among females who mated at their first estrus were compared with those among females who were first inseminated at older ages. On average, females bred at first estrus produced litters that contained more than 3 fewer pups than females mated at older ages. This observation suggests that female Sprague-Dawley rats do not attain full reproductive competence until sometime after the onset of puberty.     

Early Vaginal Opening in Juvenile Female Rats Given BRAF‐Inhibitor Dabrafenib Is Not Associated with Early Physiologic Sexual Maturation

Dabrafenib (DAB), an inhibitor of BRAF kinase activity, is approved for metastatic melanoma with a BRAF V600E mutation. In support of pediatric cancer development, a nonclinical juvenile rat toxicity study was conducted in which females had early vaginal opening (VO). It was hypothesized that the early VO was not indicative of sexual maturation, but a result of a local effect on the vagina. An investigative study was conducted that mimicked the definitive study design, with rats given DAB or vehicle orally from Postnatal Day (PND) 7 to 35 and with necropsy subsets just before VO, at the first and second estrus, along with age‐matched controls. Histopathology was performed on reproductive tissues, including immunohistochemistry for BRAF expression. VO occurred earlier in DAB females than in controls (PND 27.2 vs. 31.5); however, the timing of the first estrus was unaffected (PND 34.0 vs. 33.0). DAB‐treated females evaluated just before VO (PND 22.0) had mostly immature reproductive tracts with no evidence of ovulation, similar to age‐matched controls; however, DAB‐treated females had keratinized and histologically open vaginas. Also, there was raised skin around the urogenital area, which correlated with hyperplasia/keratosis of the vulvar skin and keratinization of the distal vagina. BRAF expression (evaluated in controls) was localized to these tissues. Thus, early VO in rats given DAB likely represents a local effect accelerating vaginal keratinization to become open and not accelerated sexual maturation     

Role of nipple stimulation in the suppression of estrous cyclicity during extended lactation in the rat

The role of nipple stimulation in the suppression of the estrous cycle during extended lactation was studied in rats subjected to either total, partial, or sham excision of the nipples. Each female cohabited with 4 pups, 4-14 days old, over a period of 70 days postpartum, during which vaginal smears were recorded daily. Initially, regardless of the presence of nipples, all rats exhibited a postpartum diestrus that lasted for 12-20 days. Intact females (bearing 6 pairs of nipples) continued to exhibit successive prolonged diestrous phases over 70 days of lactation. A comparable result was obtained with females bearing only the anterior pair of nipples, which, in a separate experiment, was found to be the most frequently suckled pair. However, females devoid of nipples resumed regular (4-day) estrous cycles between Days 12 and 27 postpartum, in spite of their continuous contact with pups. Thus, when lactation is prolonged beyond the normal time of weaning (Day 21 postpartum), stimulation of the nipples by sucking becomes indispensable for the continued arrest of the estrous cycle. The possible mechanisms underlying this phenomenon are discussed.     

Physiological pineal effects on female reproductive function of laboratory rats: prenatal development of pups, litter size and estrous cycle in middle age

The present study investigates whether and how the pineal or its hormone melatonin influences female reproductive functions, namely the litter size, prenatal development of offsprings, and estrous cyclicity, especially its age-related cessation in a non-seasonal breeder, the laboratory rat. Wistar rats were maintained under a 24 h light-dark (12Lratio12D) cycle. Female rats were divided into 3 groups: non-operated (NO), sham-operated (SX), and pinealectomized (PX). Surgeries were performed in 35-40 day-old females. Starting at an age between 70 days and 7 months, female rats of all 3 groups were repeatedly mated with intact males. PX mothers more frequently delivered pups with malformations (e.g., taillessness, hydronephrosis, 7 out of 1263 pups) than control rats (0/1323; p<0.007). In the first delivery at 3 months of age, but not at later ages, PX mothers delivered more pups of lower body weight than control animals (p<0.001). Examination of vaginal smears showed that almost all female rats of the NO, SX, and PX groups had 4-day estrous cyclicity when they were young-between 60 days and 5 months of age. At an age of 17 to 18 months, most female rats of the NO and SX groups showed irregular, continuously diestrous or pseudopregnancy-like patterns, and 4-day estrous cyclicity was found in only 10% of the NO or SX animals. In contrast, about 50% of the PX rats showed 4-day estrous cyclicity at this older age (p< 0.001). Melatonin, when added to drinking water (0.4 mg/L) for 16 days during the dark phase increased the frequency of diestrous phase, except in continuously diestrous rats and very few others. This melatonin effect was strong in PX rats but relatively weak in SX rats. In conclusion, the pineal hormone appears to influence various reproductive functions and developmental processes, especially pregnancy and the timing of reproductive aging in rats. The effects of pinealectomy are more prominent at an age of 60 to 80 days (i.e., shortly after puberty) and at the beginning of the cessation of cycles in middle-aged females.     

The peripubertal golden hamster and the transition between daily and estrous cycle hormone rhythms

Transitional patterns of LH, FSH, and progesterone (P4) in the circulation were studied in peripubertal female golden hamsters. A daily rhythm, with afternoon surges of these hormones, is typical of the immature female, whereas 4-day rhythms characterize the estrous cycle of the adult. Blood samples were collected repeatedly from maturing individuals at either 1400 or 1700 h. Each animal was examined daily for the appearance of regular vaginal estrous cycles as indicated by a mucous exudate on the morning of ovulation. Between Days -10 and -5 relative to first vaginal estrus (FVE), afternoon surges of LH, FSH, and P4 were often observed. From Days -5 to -1 relative to FVE, afternoon surges of LH and FSH were less frequent, but P4 retained the daily rhythmicity until Day -2. A 4-day pattern of LH secretion, but not of FSH or P4, was established prior to FVE. To determine whether or not ovulations were occurring prior to the appearance of external vaginal estrous cycles, reproductive tracts were collected from 26-34 days of age and examined for evidence of ovulation. Of 124 females, concordance between the record of daily vaginal examinations and the examinations of the ovaries and oviducts was found in 103 cases (83%). The development of ovarian follicles was correlated with FVE in peripubertal hamsters by unilateral ovariectomy. Antral follicles were found only in the last 3 days prior to vaginal estrus.     

Induction of increased testis growth and sperm production in adult rats by neonatal administration of the goitrogen propylthiouracil (PTU): the critical period.

We have previously shown that treating rats with the reversible goitrogen 6-propyl-2-thiouracil (PTU) from birth to Day 25 increases testis size and sperm production in adulthood by up to 80% and 140%, respectively. The purpose of this study was to determine the critical period(s) during development when PTU treatment can increase adult testis size and sperm production. Rats were treated with PTU beginning on Days 0, 8, 16, or 24 for periods of 9, 17, or 25 days. To further define the critical period, additional rats were treated with PTU prenatally or on Days 4-24. PTU treatments of 9, 17, or 25 days beginning at birth increased testis weight 18%, 38%, and 69%, respectively, by 135 days of age, while daily sperm production (DSP) increased 35%, 65%, and 94%, respectively. Efficiency of sperm production (DSP/g testis) also increased by approximately 25% in these rats. There was an inverse relationship between testis and body weights: increasing lengths of PTU treatment increased testis weight but decreased body weight. PTU treatment starting on Day 8 or later did not increase testis weight or DSP regardless of duration. Treatment on Days 4-24 increased adult testis weight and DSP similarly to treatment from birth to Day 24, but prenatal PTU treatment was ineffective. Testosterone concentrations were not altered in treated rats, even those with increased testis weight. These results indicate that the later part of the first postnatal week (Days 4-8) is the crucial period during which PTU treatment must begin in order to increase adult testis size and sperm production.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neonatal androgens influence the social play of prepubescent rats

The results of six experiments designed to investigate the hormonal basis of the sex differences in the occurrence of social play in the rat are reported. From the time of weaning animals were housed in mixed-sex, peer groups of six, composed of some treated and some untreated animals. Observations were made of the animals in these groups each day between Days 26 and 40 of life in Experiments 1, 3–6 and between Days 31 and 40 in Experiment 2. In Experiment 1 it was found that males castrated on Day 1 of life engaged in less social play than did intact males, and did not differ from normal females. In Experiment 2, castration carried out at 23 days of age had no effects on the frequency with which males engaged in social play. In Experiment 3, it was found that neonatal ovariectomy had no effect on the frequency with which female pups engaged in social play. In Experiment 4, females treated on Days 1 and 2 of life with either 250 μg of testosterone propionate or 250 μg of dihydrotestosterone engaged in social play at rates comparable to those of normal males, whereas treatment with 5 μg of estradiol benzoate had no such effect. In Experiments 5 and 6 it was found that neither the reduction of testosterone-derived estradiol (by implants of the aromatization blocker, androst-1,4,6-triene-3,17-dione) nor that of testosterone-derived dihydrotestosterone (by implants of the 5α-reductase blocker, testosterone 17β-carboxylic acid) during the early neonatal period (Days 1 to 10 of life) changed the frequency of social play in intact males. The results of these experiments indicate that the sex difference in the social play of prepubescent rats is dependent on the neonatal exposure to testosterone or to its 5α-reduced metabolite, dihydrotestosterone. The reduction of testosterone to dihydrotestosterone, however, would not appear to be a necessary step.     

Plasma progesterone concentrations and length of the first spontaneous oestrous cycle in pubertal rats

The length of the first spontaneous oestrous cycle in pubertal Wistar-Imamichi strain rats determined by vaginal smears varied from 5 to 18 days. The variation was ascribed to the period (3-16 days) of the stage of vaginal smears consisting of leucocytic cells (L stage). Plasma progesterone concentration and the decidual reaction in the uterus were used as indicators of the function of the corpus luteum and the L stage period was categorized as short, lasting for 3-6 days (average 4 days) with non-functional corpora lutea, or long, lasting 9-16 days (average 12 days) and with functional corpora lutea. Rats with the long L stage showed nocturnal and diurnal prolactin surges, but no daily changes in prolactin values were observed in rats with a short L stage. Daily changes in prolactin concentrations were maintained by the administration of progesterone in rats ovariectomized on Day 6 of the L stage. Plasma progesterone values on Day 6 of the L stage decreased with ergocornine treatment on Days 4 and 5 of the L stage and administration of bovine prolactin restored the level. These results indicate that the L stage observed in the first oestrous cycle is maintained by a positive feedback relation between progesterone and prolactin secretions.     

The timing of gonadal refractoriness in the female Turkish hamster (Mesocricetus brandti) is not dependent on the timing of gonadal regression

When prepubertal female Turkish hamsters are reared on 12L:12D, individuals respond reproductively in two ways; the majority exhibit a delay in the onset of regular vaginal estrous cyclicity (first vaginal estrus; FVE), and some individuals exhibit FVE at a time not different from females reared on 16L:8D. Soon, however, these females also become reproductively quiescent. This study addresses the following questions: (1) At what age do these two subpopulations become refractory to 12L:12D? (2) Is the onset of refractoriness in adults reared on 12L:12D dependent on the time when they become anovulatory? All females reared on 12L:12D become refractory at a similar age (169.1 +/- 4.4 days in those that exhibit delayed FVE vs. 165.3 +/- 6.8 days in those that exhibited an early FVE and then became anovulatory; p much greater than 0.05). Also, there is no correlation between the age at which vaginal cycles ceased and the age at which those individuals became refractory (r2 = 0.12; slope not different from 0). On the basis of these data, we propose that in the female Turkish hamster the onset of photorefractoriness is timed, not by the interval of reproductive quiescence, but by a preceding event, perhaps the initiation of short photoperiod exposure or the onset of photosensitivity.     

Effect of oestradiol-17 beta on ovarian and serum concentrations of relaxin during the second half of pregnancy in the rat

Immunoactivity concentrations of ovarian relaxin, serum relaxin and serum progesterone were determined from Day 12 through Day 18 of pregnancy in rats treated with oil or oestradiol-17 beta after hysterectomy or hypophysectomy and hysterectomy on Day 12. Relaxin and progesterone concentrations increased between Days 12 and 18 in sham-operated rats but failed to increase or declined in oil-treated hysterectomized or hypophysectomized-hysterectomized animals. Oestradiol treatment increased serum concentrations of relaxin and progesterone in hypophysectomized-hysterectomized rats on Day 15 and increased the concentrations of ovarian and serum relaxin and serum progesterone in hysterectomized rats on Day 18. These data are consistent with the concept that placental support for the promotion and maintenance of relaxin and progesterone concentrations from Day 12 through Day 18 may be mediated, at least in part, through a common mechanism(s) which involves oestradiol.     

Effects of perinatal polychlorinated biphenyls on adult female rat reproduction: development, reproductive physiology, and second generational effects

Perinatal exposures to endocrine-disrupting chemicals, such as polychlorinated biphenyls (PCBs), can cause latent effects on reproductive function. Here, we tested whether PCBs administered during late pregnancy would compromise reproductive physiology in both the fetally exposed female offspring (F1 generation), as well as in their female offspring (F2 generation). Pregnant Sprague-Dawley rats were treated with the PCB mixture, Aroclor 1221 (A1221; 0, 0.1, 1, or 10 mg/kg), on Embryonic Days 16 and 18. Somatic and reproductive development of F1 and their F2 female offspring were monitored, including ages of eye opening, pubertal landmarks, and serum reproductive hormones. The results showed that low doses of A1221 given during this critical period of neuroendocrine development caused differential effects of A1221 on F1 and F2 female rats. In both generations, litter sex ratio was skewed toward females. In the F1 generation, additional effects were found, including a significant alteration of serum LH in the 1 mg/kg A1221 group. The F2 generation showed more profound alterations, particularly with respect to fluctuations in hormones and reproductive tract tissues across the estrous cycle. On proestrus, the day of the preovulatory GnRH/gonadotropin surge, F2 females whose mothers had been exposed perinatally to A1221 exhibited substantially suppressed LH and progesterone concentrations, and correspondingly smaller uterine and ovarian weights on estrus, compared with F2 descendants of control rats. These latter changes suggest a dysregulation of reproductive physiology. Thus, low levels of exposure to PCBs during late fetal development cause significant effects on the maturation and physiology of two generations of female offspring. These findings have implications for reproductive health and fertility of wildlife and humans.     

Antifertility mechanisms of gossypol acetic acid in female rats

Gossypol acetic acid was administered orally (30, 60, 90 and 120 mg/kg/day) on Days 1-5 post coitum to mature female rats. At autopsy on Day 10, pregnancy in most treated animals (6/7 and 6/8) was blocked at high doses (90 and 120 mg/kg/day respectively). As the daily dose decreased to 60 mg/kg/day half (4/8) were not pregnant. However, at a lower dose (30 mg/kg/day), or at a single dose of 200 mg/kg at Day 1 p.c., pregnancy was not blocked. The concentrations of progesterone in the serum of these females were significantly decreased except at the low dose. The numbers of implantation sites in the treated females that did remain pregnant were similar to those in control females except at the dose of 120 mg/kg/day. Gossypol did not retard the development of the preimplantation embryo or cavitation. The Pontamine Blue test revealed that the drug did not interfere with the initiation of implantation. We suggest that gossypol has an antifertility effect in the female rat because it is luteolytic and disrupts post-implantation development.     

The influence of glucocorticoids during the neonatal period on the development of play-fighting in Norway rat pups

A series of experiments was designed to investigate the influence of glucocorticoids on the development of play-fighting in rat pups. Previously we have found male-typical high levels of play-fighting to depend on the presence of androgens in neonatal life. Here we report that neonatally administered glucocorticoids act to suppress these high levels of play-fighting in males. In Experiment 1, male neonates treated on either Days 1 and 2 or Days 3 and 4 of life with 300 μg of corticosterone play-fought less frequently than did oil-treated animals. Corticosterone treatment on Days 9 and 10 of life had no effect suggesting that there is a “critical period” for the corticosterone effect. Similar corticosterone treatment of female pups did not influence the frequency of play-fighting. In Experiment 2, 300 μg dexamethasone, administered on Days 3 and 4 of life, had an effect in males, comparable to corticosterone. These results suggest that there is a sex-dependent, organizational effect of glucocorticoids on the development of play-fighting in rat pups. Additional experiments showed that corticosterone treatment of males on Days 1 and 2 of life did not affect adult male sexual behavior nor did it affect levels of circulating testosterone measured on Day 3 of life. These results suggest that glucocorticoid inhibition of testosterone secretion cannot account for the effect on play behavior. The possibility that glucocorticoids act directly on neural tissues to counteract testosterone effects is discussed.