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Multiple sclerosis (MS), a demyelinating immune-mediated central nervous system disease characterized by increasing female penetrance, is the leading cause of disability in young adults in the developed world. Epidemiological data strongly implicate an environmental factor, acting at the population level during gestation, in the increasing incidence of female MS observed over the last 50 years, yet the identity of this factor remains unknown. Gestational exposure to bisphenol A (BPA), an endocrine disruptor used in the manufacture of polycarbonate plastics since the 1950s, has been reported to alter a variety of physiological processes in adulthood. BPA has estrogenic activity, and we hypothesized that increased gestational exposure to environmental BPA may therefore contribute to the increasing female MS risk. To test this hypothesis, we utilized two different mouse models of MS, experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice (chronic progressive) and in SJL/J mice (relapsing-remitting). Dams were exposed to physiologically relevant levels of BPA in drinking water starting 2 weeks prior to mating and continuing until weaning of offspring. EAE was induced in adult offspring. No significant changes in EAE incidence, progression, or severity were observed with BPA exposure, despite changes in cytokine production by autoreactive T cells. However, endocrine disruption was evidenced by changes in testes development, and transcriptomic profiling revealed that BPA exposure altered the expression of several genes important for testes development, including Pdgfa, which was downregulated. Overall, our results do not support gestational BPA exposure as a significant contributor to the increasing female MS risk.

The alkylphenol breakdown products of alkylphenol ethoxylates have been shown in in vitro studies to be weakly estrogenic, but few in vivo data address this issue in mammals. Because estrogens have been found to be most potent during developmental/perinatal exposures, this study maximized developmental exposure to nonylphenol (NP) by treating 3.5 generations of Sprague-Dawley rats to NP in diet at 200, 650, and 2000 ppm to determine the range and severity of any toxicity. Dose rate was higher for younger rats; calculated dose ranges were 9-35, 30-100, and 100-350 mg/kg/d for the low (200NP), middle (650NP), and high (2000NP) dose groups, respectively. There were adult (F0, F1, F2) and postnatal day (pnd) 21 (F1, F2, F3) necropsies; the oldest F3 rats were killed on pnd 55-58. Body weight gain was reduced by 8-10% in the 650NP and 2000NP groups. Vaginal opening was accelerated by approximately 2 days (650NP) and approximately 6 days (2000NP) in F1, F2, and F3 generations. Uterine weights at pnd 21 were increased in 650NP (14%) and 2000NP (50%) F1 females, but not in other generations. Testis descent, anogenital distance, and preputial separation were not consistently changed. No consistent changes were seen in pup number, weight or viability, litter indices, or other functional reproductive measures. Relative ovary weight in F2 adults was decreased at 650NP and 2000NP by 12%; relative ovary was unchanged in other generations. Follicle counts were unchanged in F2 adults. Sperm indices, including CASA measures, were unchanged in F0 and F1 males. In F2 rats, epididymal sperm density was reduced by 8% and 13% at 650NP and 2000NP, respectively. Testicular spermatid count was reduced by 13% in 2000NP F2 males; testis and epididymis weights were unchanged. Erosion of gastric and duodenal mucosa was monitored grossly and microscopically, and never found. Kidney weights were increased in 650NP and 2000NP males, and renal medullary tubular dilatation and cyst formation were noted in all generations of males, and often at the lowest dose tested. These data show that NP had limited effects on the reproductive system in the presence of measurable nephrotoxicity. The F2 sperm effects are either statistical/biological "noise," or imply heretofore unknown pharmacokinetics or toxicodynamics. These sperm data should be interpreted cautiously until the findings are repeated.

Ethylene glycol monomethyl ether (EGME) and its proximate metabolite, 2-methoxyacetic acid (MAA), increase ovarian luteal cell progesterone production in the female rat in vivo and in cultured rat luteal cells in vitro, respectively. In order to better assess the potential hazard of EGME and MAA to women, these studies were conducted to determine whether the same concentrations of MAA increase progesterone in human luteinized granulosa cells as in rat luteal cells. Human cells were collected from healthy anonymous oocyte donors, washed, plated 25,000 viable cells per well, and treated with 10 IU hCG and 0–5 m m MAA for 6–48 hr. Progesterone in media was significantly elevated after 24 hr incubation at ≥1 m m MAA. MAA had no effect on ATP levels at 6 or 24 hr. Thus, MAA increased progesterone production in cultured human luteal cells at the same concentration as MAA increased progesterone in rat luteal cells. The implication is that EGME has the potential to alter ovarian luteal function in women. These data should be useful for determining the real health hazards and potential risks of EGME exposure.

Indium is increasingly used in a variety of industries, and while there are few studies of its developmental toxicity, ther are no reports of its potential reproductive toxicity. These studies were undertaken to investigate the possible reproductive toxicity of indium and to determine the relative vulnerability of males and females. We used, initially, a 21-day combined developmental/reproductive toxicity protocol. Oral exposures to InCl3 ( < or = 250 mg/kg) were without effect on the male reproductive system or liver. A kidney effect was demonstrated in males by a decrease in urinary N-acetyl glucosaminidase. The ability of females to become pregnant was unaffected. However, fetal development was adversely affected, manifested as increased intrauterine deaths in the presence of reduced maternal weight gain. A developmental toxicity study identified no increase in fetal malformations, but verified the increased fetal deaths, in the absence of effects on adjusted maternal body weight. In vitro toxicity studies showed that the embryolethality was at least in part a result of direct toxicity to the conceptus, with effective doses in the low micromolar range. A limited disposition study showed that fetuses contained low micromolar concentrations of indium, more indium than maternal liver, and comparable to levels that were toxic in vitro. Although studies of greater exposure duration are required for risk assessment, these data indicate that fetal development is likely to be more affected by indium than female or male reproduction, with adverse effects occurring at low micromolar levels in vivo and at exposures that may or may not affect body weight.