Bisphenol A: developmental toxicity from early prenatal exposure.

Bisphenol A (BPA) exposure has been documented in pregnant women, but consequences for development are not yet widely studied in human populations. This review presents research on the consequences for offspring of BPA exposure during pregnancy. Extensive work in laboratory rodents has evaluated survival and growth of the conceptus, interference with embryonic programs of development, morphological sex differentiation, sex differentiation of the brain and behavior, immune responsiveness, and mechanism of action. Sensitive measures include RAR, aryl hydrocarbon receptor, and Hox A10 gene expression, anogenital distance, sex differentiation of affective and exploratory behavior, and immune hyperresponsiveness. Many BPA effects are reported at low doses (10-50 µg/kg d range) by the oral route of administration. At high doses (>500,000 µg/kg d) fetal viability is compromised. Much of the work has centered around the implications of the estrogenic actions of this agent. Some work related to thyroid mechanism of action has also been explored. BPA research has actively integrated current knowledge of developmental biology, concepts of endocrine disruption, and toxicological research to provide a basis for human health risk assessment.

Reduced water intake: Implications for rodent developmental and reproductive toxicity studies.

In developmental and reproductive toxicity studies, drinking water is a common means of delivering the test agent. Reduced consumption of toxicant-containing water raises questions about indirect effects of reduced maternal fluid consumption resulting from unpalatability, versus direct effects of the test compound. Issues to consider include: objective assessment of dehydration and thirst, the relative contributions of innate and learned behaviors to drinking behavior and flavor preference, and the objective assessment of physiologic stress. Not only do lab animals under ad lib conditions consume more water than the minimum required to maintain fluid balance, animals faced with water restriction have substantial physiologic capacity for protection of metabolic processes. Measures of blood biochemistry can provide quantifiable, objective indications of fluid balance, but changes in these parameters could result from other causes such as effects of a test toxicant. Consummatory behaviors in response to perceived need are highly influenced by learning. Hence, the drinking behavior, water intake, and flavor acceptance/preference of animals used in toxicology experiments could be subject to learning experiences with the test compound. Physiological symptoms of stress produced by water deprivation may be distinguishable from the symptoms associated with other generalized stressors, such as food deprivation, but doing so may be beyond the scope of most developmental or reproductive toxicity studies. Use of concurrent controls, paired to test groups for water consumption, could help distinguish between the direct effects of a test toxicant as opposed to effects of reduced water consumption alone.

"Natural" progesterone: information on fetal effects.

BACKGROUND: A variety of progestational agents have been used therapeutically and evaluated for adverse effects over the last 50 years. However, progesterone itself has come into use as a therapeutic agent only recently with the development of an orally bioavailable "micronized" preparation. METHODS: The current review examines progesterone adverse effects as identified in the larger literature on the toxicity of progestational agents and pharmacokinetics. RESULTS: Progesterone has cytoplasmic and membrane receptors in a variety of reproductive and nonreproductive tissues including the brain and is a potent inhibitor of GnRH. Limited information is available on progesterone receptors and actions in the fetus. Concern about exogenous progestagen effects on fetal reproductive tract development have led to considerable human research over the years, but this literature review demonstrates that contemporary developmental toxicology research on progesterone is lacking. CONCLUSIONS: Progesterone is a potent, multi-faceted endocrine agent with an expanding therapeutic profile and a minimal scientific database for evaluating safe use during pregnancy.

Environmental tobacco smoke and pregnancy outcome.

BACKGROUND: Recent reviews conclude that environmental tobacco smoke (ETS) leads to diminished birth weight. However, the threshold and magnitude of that effect is uncertain. We aimed to determine the magnitude and shape of the relations between ETS and various adverse pregnancy outcomes using a highly sensitive biochemical assay. METHODS: Maternal serum specimens were collected from more than 3000 women enrolled in California's prenatal screening program in 1992 and analyzed for cotinine. Information on pregnancy outcomes was obtained from live birth/fetal death records and hospital questionnaires. We conducted analyses on 2777 woman-live birth pairs and 19 woman-fetal death pairs in which the mother was presumed to be a nonsmoker (midtrimester cotinine levels < or =10 ng/mL). RESULTS: In multiple logistic regression analyses, the odds ratios of fetal death, preterm delivery, and term-low birth weight were 3.4, 1.8, and 1.8, respectively, in the highest cotinine quintile (0.236-10 ng/mL), compared with the lowest quintile (<0.026 ng/mL). In adjusted linear models, there was a linear dose-dependent effect of log cotinine on mean birth weight (-109 g) and mean infant length (-0.84 cm) over the range of cotinine values. Linear relations were not found with respect to infant head circumference or the ratio of brain weight to body weight. Infant's body mass index declined with exposures above approximately 0.5 ng/mL cotinine. We estimated that ETS levels at or above 0.05 ng/mL (experienced by 62% of the study population) accounted for 12% of all adverse outcomes. CONCLUSIONS: ETS exposure in pregnant women adversely affects pregnancy by increasing fetal mortality and preterm delivery at higher exposure levels and slowing fetal growth across all levels of ETS exposure.

Effects of restraint stress in gestation: implications for rodent developmental toxicology studies.

Restraint has been used as a procedure to study the effects of stress on gestation outcome in rodents. The effects of restraint could potentially be used as a model for the impact of general stress produced by high doses of toxicants and other interventions. In mice, restraint in the peri-implantation period leads to implantation failure, and restraint at appropriate times in organogenesis produces cleft palate, supernumerary ribs, and resorption. In rats, there is some evidence for an association with restraint for implantation failure, but not for the morphological anomalies. Restraint in late gestation alters adult sexual behavior of male rat offspring, but consequences for their fertility are not known. Intrauterine growth retardation is not commonly associated with gestational restraint. In the few studies where they have been directly compared, different restraint procedures produced graded, qualitatively different, or no effects. Adrenocortical hormones have been implicated as mediating the effect of restraint on cleft palate, but not on supernumerary ribs, implantation failure, or sexual differentiation. Given the variety of restraint procedures and the varying species-dependent consequences, it is not possible to infer a generalizable pattern of developmental effects due to gestational stress from the restraint literature. As an alternative approach, contemporary methods in gene expression and developmental biology could profitably be applied to understanding different patterns of stress-mediated effects of toxicant exposures on intrauterine development.

Exposure to environmental tobacco smoke in pregnant women: the association between self-report and serum cotinine.

The risk of delivering a low-birth-weight infant as the result of exposing a nonsmoking pregnant woman to environmental tobacco smoke (ETS) is not well defined. The method of ascertaining ETS exposure during pregnancy may explain the lack of consistent study findings. In a large sample of pregnant women, we compared distributions between two methods of ETS exposure: self-report and cotinine, a nicotine metabolite, from serum. At livery, subjects were asked about duration and location of exposure to ETS during their second trimester. A single cotinine measurement was assayed from serum collected at 15-19 weeks gestation (limit of detection=0.05 ng/mL). Self-reported (hours per day) ETS exposure was correlated (r=0.38) with cotinine concentration. Regression analysis revealed that while self-reported ETS was significantly associated with (log) cotinine, it did not explain a large amount of total variation. While 72% of subjects reported no exposure to ETS, almost all had measurable levels of cotinine. Studies of pregnant women based upon an hours per day ETS question have likely misclassified a sizable portion of ETS-exposed women as "unexposed." Since there is recent evidence that low levels of ETS exposure result in unfavorable pregnancy outcomes, these studies have underestimated the effect of ETS.