Exposure to bisphenol A (BPA) is implicated in many aspects of metabolic disease in humans and experimental animals. We fed pregnant CD-1 mice BPA at doses ranging from 5 to 50,000 μg/kg/day, spanning 10-fold below the reference dose to 10-fold above the currently predicted no adverse effect level (NOAEL). At BPA doses below the NOAEL that resulted in average unconjugated BPA between 2 and 200pg/ml in fetal serum (AUC0–24h),we observed significant effects in adult male offspring: an age-related change in food intake, an increase in body weight and liver weight, abdominal adipocyte mass, number and volume, and in serum leptin and insulin, but a decrease in serum adiponectin and in glucose tolerance. For most of these outcomes non-monotonic dose–response relationships were observed; the highest BPA dose did not produce a significant effect for any outcome. A 0.1-μg/kg/day dose of DES resulted in some but not all low-dose BPA outcomes.

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Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous environmental contaminant. Epidemiological studies suggest that DEHP decreases masculinization of male fetuses. Numerous rat studies report DEHP reduces fetal testosterone production at doses greatly exceeding human exposure. We fed pregnant CD-1 mice 0.5 - 500,000 μg/kg/day DEHP from gestation day (GD) 9 - 18 and examined mothers and male fetuses on GD 18. We assessed non-monotonic dose-response by adding a quadratic term to a simple linear regression model. Except at the 500,000-μg/kg/day dose, DEHP stimulated an increase in maternal and fetal serum testosterone and increased anogenital distance (AGD). Non-monotonic dose-response curves were noted for AGD and maternal, and testis testosterone (p values 0.013 to 0.021). Because data from our highest dose (500,000-μg/kg/day) did not differ significantly from controls, this dose could have been incorrectly assumed to be the NOAEL had we only tested very high doses, as is typical in studies for regulatory agencies.

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