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The authors evaluate possible use of Monchegorsk retrospective birth database for demographic and epidemiologic studies of various female reproductive health parameters, newborn health parameters, as well as their connections with occupational and other environmental factors.
Many biochemical endpoints currently are used to describe endocrine function in fish; however, the sensitivity of these parameters as biomarkers of impaired reproduction or sexual development is not well understood. In the present study, adult Japanese medaka (Oryzias latipes) were assessed for reproductive output and endocrine function, including circulating steroid concentrations, ex vivo steroidogenesis from the gonads, aromatase activity, hepatic estrogen receptor (ER), and plasma vitellogenin (VTG) after exposure to 0, 0.2, 5, 500, and 2,000 ng/L of 17alpha-ethinylestradiol (EE) for 14 d. The EE altered these biochemical responses at various sites along the hypothalamus-pituitary-gonadal axis at concentrations as low as 0.2 ng/L, but it only depressed reproductive function at concentrations of 500 ng/L or greater. Offspring also had reduced ability to hatch at 500 ng/L of EE, but this concentration did not produce any other observed changes in development or sexual phenotype. The reproductive parameters correlated well with VTG, ER, and gonadosomatic index (GSI) in both sexes of adult medaka, which could be indicative of the ER-mediated mode of action for EE. Vitellogenin and ER were elevated at higher concentrations of EE in both sexes, whereas GSI was decreased. Overall, most biochemical endpoints were more sensitive than reproduction or development to exposure, indicating that reproductive function may be relatively protected.
A recent study further investigated the potential effects of maternal thyroid function and morphology on fetal development upon maternal exposure to ammonium perchlorate during gestation and lactation. Female Sprague-Dawley rats (25/group) were given continual access to 0 (carrier), 0.01, 0.1, 1.0, and 30.0 mg/kg-day perchlorate in drinking water beginning 2 weeks prior to cohabitation through lactation day 10. Maternal, fetal, and pup serum thyroid hormone (thyroid-stimulating hormone [TSH], triiodo thyronine [T(3)], thyroxine [T(4)]) levels and thyroid histopathology were evaluated on gestation day 21, and lactation days 5, 10, and 22. No effects of exposure were observed on cesarean-sectioning, litter parameters, or fetal alterations. Reproductive parameters, including gestation length, number of implants, litter size, pup viability, and lactation indices, were comparable among all groups. Thyroid weights of dams sacrificed on gestation day 21, and lactation days 10 and 22 were significantly increased at 30.0 mg/kg-day. Increased thyroid weights were observed in male and female pups as early as postpartum days 5 and 10, respectively. Changes in maternal and neonatal thyroid histopathology were detectable at 1.0 mg/kg-day exposure. The maternal no-observable-effect level (NOEL) was 0.1 mg/kg-day (follicular cell hyperplasia was present at 1.0 and 30.0 mg/kg-day). The developmental NOEL was less than 0.01 mg/kg-day; thyroid weights of postpartum day 10 pups were increased at all exposures. Colloid depletion at 1.0 and 30.0 mg/kg-day exposures and changes of hormone levels at all exposures were considered an adaptive effect and appeared reversible in the rodent.
Increased occurrence of reproductive disorders has raised concerns regarding the impact of endocrine-disrupting chemicals on reproductive health, especially when such exposure occurs during fetal life. Prenatal testosterone (T) treatment leads to growth retardation, postnatal hypergonadotropism, compromised estradiol-positive feedback, polycystic ovaries, and infertility in the adult. Prenatal dihydrotestosterone treatment failed to affect ovarian morphology or estradiol-positive feedback, suggesting that effects of prenatal T may be facilitated via conversion of T to estradiol, thus raising concerns regarding fetal exposure to estrogenic endocrine-disrupting chemicals. This study tested whether fetal exposure to methoxychlor (MXC) or bisphenol A (BPA) would disrupt cyclicity in the ewe. Suffolk ewes were administered MXC (n=10), BPA (n=10) (5 mg/kg.d sc in cotton seed oil) or the vehicle (C; n=16) from d 30 to 90 of gestation. On d 60 of treatment, maternal MXC concentrations in fat tissue and BPA in blood averaged approximately 200 microg/g fat and 37.4+/-3.3 ng/ml, respectively. Birth weights of BPA offspring were lower (P<0.05) relative to C. There was no difference in the time of puberty between groups. BPA females were hypergonadotropic during early postnatal life and ended their breeding season later, compared with C. Characterization of cyclic changes after synchronization with prostaglandin F2alpha in five C, six MXC, and six BPA females found that the onset of the LH surge was delayed in MXC (P<0.05) and the LH surge magnitude severely dampened (P<0.05) in BPA sheep. These findings suggest that prenatal BPA and MXC exposure have long-term differential effects on a variety of reproductive endocrine parameters that could impact fertility.
Little is known about the ecotoxicological hazard of cadmium to wild small mammals. This paper reviewed laboratory and field studies to determine: (i) intake and residue lowest-observable-adverse-effect-levels (LOAELs) for the ecologically important parameters of reproduction and development; (ii) whether these LOAELs are exceeded by wild small mammals on contaminated habitats and what adverse effects result; and (iii) which species may be at most risk from cadmium. The intake LOAEL in laboratory rodents was 3.5-7.5 mg kg-1 body wt day-1 and the residue LOAEL, based on cellular damage in the kidney, was a renal cadmium concentration of 105 mg kg-1 dry wt. On contaminated habitats, these LOAELs are exceeded by common shrews Sorex araneus but not by wild rodents. However, there is little evidence of adverse cadmium-mediated effects in common shrews and this species may be tolerant to cadmium exposure. Large cadmium concentrations in body organs may simply reflect an ability to store cadmium in a nontoxic, metallothionein-bound state. In contrast, studies suggest that microtine voles may be sensitive to cadmium and, despite their relatively low cadmium intake and accumulated residues, may suffer adverse effects. The need to establish dose-residue-effect relationships for intakes and residues which are appropriate for wild species and also based on ecologically important parameters is discussed.
Testicular regression was induced in adult golden hamsters by exposure to a short photoperiod (5 h light:19 h darkness). The response of these animals to exogenous steroids (ten injections each of 5 mg testosterone, testosterone propionate, pregnenolone, progesterone or cortisol administered s.c. three times/week) was evaluated from weight changes in testes and seminal vesicles, from plasma levels of LH, FSH and testosterone, and from testicular human chorionic gonadotrophin (HCG) binding and testosterone levels. Administration of testosterone or testosterone propionate produced a decrease in plasma gonadotrophins and a three- to fourfold increase in weights of testes and seminal vesicles, thus indicating that the seminiferous tubules, similarly to accessory reproductive glands, retained the ability to respond to androgenic stimulation. Binding of HCG by testicular tissue was dramatically reduced by treatment with testosterone, probably reflecting atrophy of the Leydig cells. Treatment with pregnenolone or progesterone failed to increase testicular weight, seminal vesicle weight or concentrations of in the testes. This suggests that the atrophic testes of these animals may have a limited capacity to produce biologically significant amounts of androgens from C21 steroids. Administration of cortisol did not alter any of the parameters of reproductive function that were examined.
We investigated the effects of stress over the final stages of sexual maturation on the reproductive performance of female rainbow trout, Oncorhynchus mykiss. Stress was administered over the period of early vitellogenesis (1.5 mo), late vitellogenesis-final maturation (1.5 mo), or during both periods (3 mo). Each stress treatment and control was triplicated, with eight females in each replicate (n = 24 fish per treatment). The eggs and progeny of each female were kept separate, and observations were made for 4 mo after transfer to rearing tanks. Fish that experienced stress during final maturation and those that were under stress during the whole experiment ovulated on average 2 wk earlier than the control group. In contrast, fish stressed during the period of early vitellogenesis ovulated at the same time as controls. Absolute fecundity and fertilization were not significantly affected in any treatment group, but significant differences in relative fecundity were found. Stress applied early in vitellogenesis resulted in smaller eggs and swim-up fry. No significant differences were found in juvenile weight 8 wk after hatching. Furthermore, we found no differences in survival of the progeny or resistance to the fish pathogen Vibrio anguillarum. Thus, mild acute stresses applied to rainbow trout females may affect certain reproductive performance parameters such as timing of ovulation and relative fecundity; however, the progeny of such stressed females perform as well as controls with regard to juvenile growth and disease resistance.
Tricresyl phosphate (TCP) is used commercially as a plasticizer and a flame retardant. The reproductive effects of TCP (less than 9.0% TOCP) were examined. Male Long-Evans rats received 0, 100, or 200 mg/kg and females received 0, 200, or 400 mg/gk TCP in corn oil by gavage. The 100 mg/kg TCP males were mated with 200 mg/kg TCP females, and 200 mg/kg TCP males were bred with 400 mg/kg TCP females. Males were dosed for 56 days and females for 14 days prior to breeding and throughout the 10-day breeding period. Following breeding, the males were necropsied and evaluated for sperm parameters and reproductive tract histopathology. Females were dosed throughout gestation and lactation. Pups and adult females were necropsied on postnatal day 21. Sperm concentration, motility, and progressive movement were decreased for 200 mg/kg dose group males. A dose-dependent increase in abnormal sperm morphology was observed for males in both TCP dose groups. The percent of sperm-positive females per group was unchanged, but the number of females delivering live young was severely decreased by TCP exposure. Litter size and pup viability were decreased in the 400 mg/kg dose group. Pup body weight and developmental landmarks were unaffected by TCP exposure. Histopathologic changes were observed in the testes and epididymides of male rats and in the ovaries of female rats exposed to TCP.
"This paper presents a microanalytic stochastic model of human reproduction with special features for use in examining reproduction in high mortality populations. The model builds on prior work by including (a) a beta distribution for fecundability, permitting variations between women and during a woman's childbearing years, (b) fetal deaths and stillbirths that vary with a woman's age, and (c) sterility that varies as a function of two random probability distributions. New to this model is inclusion of a Weibull survival function for infant and child mortality and a model schedule of postpartum amenorrhoea that depends on the length of breastfeeding." Consideration is given to the interaction of breast-feeding and early mortality and their effects on human reproduction. "Input parameters are selected for the population of Bangladesh, and initial results from a Monte Carlo simulation, in which age at marriage varies, are given."
Colesevelam hydrochloride (HCl) (WelChol; Sankyo Pharma) is a novel, highly potent, bile acid-binding polymer used for the treatment of hypercholesterolemia. The primary aim of this study was to determine the effects of dietarily administered colesevelam HCl on fertility and reproductive performance parameters. To assess these effects, sexually mature Sprague-Dawley rats were randomized to one of five treatment groups: feed alone, feed plus control article (SigmaCell), or feed plus colesevelam HCl 200, 1000, or 2000 mg/kg/day. Male and female rats were administered the appropriate group agent for 28 and 15 days, respectively, and were subsequently paired together for cohabitation and mating. Females continued to receive the test agent in their dietary formulation through presumed gestation day (GD) 7. Presumed pregnant females underwent cesarean section on GD 20. Food consumption rate, body weight, gross necropsy, and standard preclinical tests for reproduction and fertility were performed for each test animal. No statistically significant differences were found between control and drug-treated groups for any tested endpoints of reproduction. All animals placed in cohabitation successfully mated. Uterine and litter end points were unaffected by dosages of colesevelam HCl as high as 2000 mg/kg/day. There were no significant differences between treatment group litter averages in the number of corpora lutea, implantation sites, litter size, live fetuses, body weights, early/late resorptions, and the number of dams with viable fetuses. In addition, no external alterations of fetal morphology were attributable to treatment with colesevelam HCl when administered up to the embryo implantation stage. In male animals, no significant differences were found between the colesevelam HCl and control study groups in the average caudal epididymal sperm count or sperm concentration, total number of motile and nonmotile sperm, and the total percentage of motile sperm. Based on these data, colesevelam HCl does not have any significant adverse reproductive or fertility effects in rats, even when administered at doses approximately 30 times greater than the approved clinical dose.
Certain chlorine-substituted sugars with chemical similarities to sucralose have been demonstrated previously to diminish or inhibit sperm glycolysis and fertility in the rat ([Ford]). In order to investigate this potential for sucralose, epididymal spermatozoa were recovered from rats exposed in vivo to oral doses of one of three of these substituted sugars: 6-chloroglucose (6-CG, 24mg/kg/day, positive control), sucralose (500mg/kg/day, over 300 times the expected human daily intake), or a 6'-substituted isomer of sucralose, trichloro de-oxy sucrose (TCDS, 100mg/kg/day, a potential trace impurity in commercial sucralose); distilled water served as the negative control. After incubation of the spermatozoa with D-[U-(14)C] glucose, measurements of (14)CO(2) and of ATP content showed no impairment of the glycolytic ability of spermatozoa in any of the groups except for a marked inhibition for those exposed to 6-CG, the positive control. In order to determine whether other parameters of reproduction and fertility could be affected, reproductive endpoints were examined following oral exposure of male and female rats to sucralose. Sucralose was fed in the diet at concentrations of 0, 0.3, 1.0 and 3.0% (approx. 100, 365 and 1150 times the EDI) to groups of 30 male and 30 female rats for 10 weeks prior to mating, and continued through two subsequent generations until weaning of the F(2) pups. Two litters were produced per generation. Food consumption and weight gain in the F(0) and F(1) generations were depressed in all sucralose groups before mating and in all four litters prior to weaning. The decrease in initial average weight for newborn pups probably reflects the increased litter sizes noted for sucralose-treated groups and the reduced food consumption of the dams during gestation and lactation. The latter is a result primarily of the unpalatability of sucralose to rats ([McNeil,]). Caecal enlargement (a common animal response to large doses of indigestible material) occurred in both the F(0) and F(1) parents. Increased kidney weights, possibly associated with increased water intake, were observed primarily among animals receiving 3% sucralose (no renal histopathology has been detected). Decreased thymus weights occurred in F(1) males and in both F(1) and F(2) females at the 3% level. Subsequent studies specifically designed to investigate the potential for adverse immune system effects of sucralose ([McNeil,]) showed no adverse effects. These findings are consistent with investigations by others showing that decreases in thymus weights occur in young rats in response to stressful conditions associated with reductions in weight gain. All reproductive indices (oestrous cycles, mating behaviour, fertility, gestation, maternal and foetal viability, foetal development, parturition, pup maturation and lactation) were comparable between the control and sucralose-treated groups. We conclude from these results that sucralose has no effect on sperm glycolysis or on male or female reproductive performance in the rat.
Reproduction has major influence on productivity of beef cattle operations. Maintaining an animal in the herd for an extended period without producing a marketable product can result in significant economic losses, compromising the efficiency of the production system. Understanding genetic variation's role in pregnancy loss (PL) is crucial for improving reproductive success in cattle. Identifying genomic regions that influence embryo and fetal survival, as well as pinpointing candidate genes associated with PL, can enhance breeding strategies. The objective of this study was to estimate variance components and investigate genetic factors associated with PL in Brahman cattle. Phenotypic records consisted of 29,905 pregnancy (28,691) and abortion (1,214) records from nulliparous, primiparous, and multiparous cows. A total of 921 animals were genotyped using a medium-density SNP chip (∼52K markers). Variance components were estimated using a threshold model to assess the binary response to PL through a single-step genomic BLUP procedure. The heritability estimate for PL was low (0.11), but the presence of genetic variance suggests that selection for improved reproductive performance is feasible. Genome-wide association analyses identified 17 candidate regions containing 92 genes. Regions on BTA4, 7, 8, 9, 11, 12, 16, 18, 19, 21, 22, and 29 harbored genes associated with embryonic development and implantation, fertilization, G protein-coupled receptors, embryonic brain development, olfactory receptor activity, and calcium signaling. Orthologous genes were also identified in humans (Homo sapiens), rats (Rattus norvegicus), and mice (Mus musculus). The candidate regions reported in this study provide insights for identifying and selecting animals with improved reproductive performance, ultimately enhancing the productivity of Brahman cattle. Moreover, our findings contribute to a better understanding of the genetic and physiological mechanisms underlying pregnancy retention in beef cattle.
Chlorpyrifos-methyl (CPM) suppressed androgenic activity in Hershberger assay using castrated rats. Acute oral lowest-observed-adverse-effect-level (LOAEL) and no-observed-adverse-effect-level (NOAEL) was evaluated as 12 and 0.1 mg/kg bw, respectively, based on its major effect of cholinesterase inhibition. Also, repeated oral NOAEL was 0.1 mg/kg bw/day based on adrenal damage in rats. We investigated one-generation reproductive toxicity of CPM focusing on endocrine-disrupting effects by the administration of 1, 10 and 100 mg/kg bw/day CPM to mature SD rats (F0) through pre-mating, mating, gestation and lactation period and to their offspring (F1) until 13 weeks age via gavage. A group treated with corn oil served as vehicle control. In F0 rats, the most affected organs were adrenal glands as increased in weight at all doses of CPM in males and at 10 and 100 mg/kg CPM in females and adrenal vacuolation at CPM 10 and 100 mg/kg. The relative and absolute ovaries and the absolute seminal vesicle weights were decreased but the weights of liver, spleen or kidneys were increased at 100 mg/kg CPM. Parameters representing reproductive performances as mating ratio, gestation length and delivery index were not affected, except for decreased fertility index and numbers of implantation and born pups and a higher male sex ratio of pups at CPM 100 mg/kg. F1 pups exposed to CPM 100 mg/kg in utero and via maternal milk showed lower body weight with changes of absolute or relative weights of brain, ovary, liver, spleen and epididymis and decreased absolute not relative anogenital distance at weanling time. The time of vaginal patency and preputial separation and estrous cycling pattern of F1 rats were not impacted by CPM. After further 10 weeks oral administration until 13 weeks old, adrenal glands, brain, liver, spleen or kidneys tended to be increased, while thyroid gland, testes and ventral prostate of F1 male rats were decreased at CPM 10 or 100 mg/kg. Histopathologically, necrosis or vacuolation of thyroid follicular epithelial cells and adrenal cortical cells were observed at all doses of CPM. Serum levels of estradiol, testosterone, T4 and T3 were significantly lower while TSH and cholesterol were higher in both F1 female and male rats treated with CPM though dose-responsiveness was not clear in F1 females. Decreased sperm were counted in F1 rats at CPM 100 mg/kg. As a whole, LOAEL and NOAEL was evaluated as 10 and 1 mg/kg bw, respectively, based on decreased estradiol and T4 and increased TSH in serum of F1 male rats, and when considering histopathological alteration of adrenal and thyroid glands, LOAEL assumed to be lower than 1 mg/kg bw. This study elucidates that CPM exhibit weak reproductive toxicity in F0 rats exposed at adulthood and negligible effects in F1 offspring exposed in utero and via lactation at weanling, but induce anti-androgenic effect and hypothyroidism after long term exposure from in utero through sexual maturation of F1 rats.
The inverse relationship between mammalian fetal weight and litter size has been discussed by many authors, but their opinions reveal no agreement at all. As in toxicity studies of reproduction, both parameters must be correctly evaluated. We investigated the existence of such a relationship in 2466 fetuses from 203 litters of Sprague-Dawley CD control rats. The frequency distribution of fetal weights had a normal adjustment. From the mean weight of fetuses in each litter, the mean fetal weights in each litter size and correlation coefficient were calculated and the regression line was plotted; the correlation coefficient (r = 0.677) was highly significant (P = 0.002), which made evident that there was an inverse relationship between fetal weight and litter size. If fetal weight/litter size inverse relationship is not taken into account when toxicity on the fetal weight is analyzed, wrong conclusions may be reached if the test substance reduces the litter size, provoking embryofoetal mortality. The iatrogenic decrement in fetal weight can be masked by an increment due to the litter size reduction. We suggest that in all three segments of reproductive toxicity studies, litter size must be considered as a covariate to the effect of the test substance on the fetal weight, in order to perform a correct analysis of covariance (ANCOVA), in addition to the dose factor commonly used in common ANOVA.
The effects on food intake, growth and reproductive performance parameters of defatted jojoba meal and pure simmondsin, an extract from jojoba meal, were compared in female Wistar rats. Rats fed 0.15% simmondsin or 3% defatted jojoba meal (equivalent to 0.15% simmondsin) for 8 weeks before conception showed a similar reduction in food intake (about 20%) and a similar growth retardation compared with controls. Both treatments induced a reduction in the number of corpora lutea on gestation day 16: this effect could be ascribed to the lower food intake before conception because it was also observed in rats pair-fed to the treated ones. Rats given feed containing 0.15% simmondsin or 3% defatted jojoba meal during days 1-16 of gestation showed a similar reduction in food intake relative to controls. Foetal and placental weights were reduced, relative to controls, to a similar extent in both groups, and the reductions were slightly greater than in the corresponding pair-fed groups. We conclude that the effects on food intake, growth and reproductive performance that were seen after feeding rats defatted jojoba meal were due to the simmondsin content of the meal. The simmondsin induced reduction in food intake and probably also a relative protein shortage.
Bromantan is a new psychostimulator possessing actoprotector properties. The drug was administered to rats over two months (males) and two weeks (females) at a daily dose of 30 and 200-mg/kg, and the reproduction function parameters were monitored. Then the experimental animals were coupled and the embryonal characteristics of the breed were determined. Upon termination of the drug administration, the functional state of sperm and the morphology of gonads were studied again. It was found that bromantan (30 mg/kg) unreliably decreases the absolute amount of sperm in males. In females, the drug did not affect the ovary weight coefficient and increased the gestation index. After termination of the drug administration, the ovary weight coefficient increased. Bromantan affected neither the fertilizing capacity of male and female gametes nor the embryonal characteristics of the breed.
BACKGROUND: Historical control data play a crucial role in the interpretation of observations made from developmental and reproductive toxicity studies. METHODS: In our effort to develop the Dutch-Belted rabbit as an alternative breed of rabbit for testing of small molecule pharmaceuticals, data collected from 236 untreated pregnant Dutch Belted rabbits are summarized and compared to data collected from 350 untreated pregnant New Zealand White Rabbits. RESULTS: The data presented include mean maternal body weight and food consumption values, mean maternal hematological and serum biochemical values collected during gestation, maternal reproductive (laparotomy) parameters collected at cesarean section, and incidences of spontaneous fetal morphological alterations collected during 1999-2002. Due to their smaller size the use of this breed of rabbit would require approximately 40% less drug than studies conducted with New Zealand White rabbits. Because the Dutch-Belted rabbit is pigmented this breed also offers the ability to test the potential effects of various xenobiotics on melanocyte development and to evaluate the potential sequela of drugs that have a propensity to bind melanin in the skin and pigmented retinal epithelium. CONCLUSIONS: Based on these data, the Dutch-Belted rabbit is considered to be a practical alternative to use of the New Zealand White rabbit for these types of studies.
We examined multiple aspects of reproductive function in growth hormone receptor gene knockout (GHR-KO) and normal mice to clarify the role of growth hormone in female reproduction. In adult animals, estrous cycle duration was comparable in all mice housed individually but was significantly longer in group-housed GHR-KO females. Histological evaluation of ovaries of adult females at estrus showed that the numbers of preovulatory follicles and corpora lutea were significantly reduced in GHR-KO mice, as was the plasma estradiol level. The number of atretic preovulatory follicles was reduced in GHR gene-ablated animals. Although reverse transcription polymerase chain reaction analysis revealed reduced ovarian insulin-like growth factor I (IGF-I) mRNA expression in GHR-KO females, the expression of several steroidogenic enzyme mRNAs did not differ between groups. The numbers of active corpora lutea and uterine implantation sites were reduced in GHR-KO females at Day 7 of gestation. When young females were mated to normal males, latency to first mating and age of the female at first mating were significantly delayed in GHR-KO females, but maternal age at first conception was similar between groups. Significantly fewer virgin GHR-KO females exhibited pseudopregnancies when initially placed with vasectomized normal males than did normal female counterparts. Growth hormone resistance and IGF-I insufficiency negatively impacted 1) follicular development/ovulation rate, 2) sexual maturation, 3) production of and responsiveness to pheromonal signals, and 4) the ability of virgin females to respond to coitus by activation of luteal function. Although GHR-KO female mice are fertile, they exhibit quantitative deficits in various parameters of reproductive function.