Maternal exposure to a mixture of Bisphenol A and Diethyl Hexyl Phthalate predisposes female offspring to growth retardation and metabolic dysfunction in adulthood

Abstract

Background A newly recognized primary cause of the obesity epidemic is the developmental programming effects of plastic-derived environmental contaminants, Bisphenol A (BPA) and Diethyl-Hexyl-Phthalate (DEHP), which are known to be endocrine disrupting chemicals (EDCs). Research addressing the effects of a mixture of these EDCs is limited. Objective To assess the metabolic consequences of developmental exposure to individual as well as mixtures of BPA and DEHP in female Sprague-Dawley rats. Methods From gestational days 6-21, pregnant Sprague Dawley dams were orally administered either saline (control), BPA (5mg/Kg BW/day), DEHP (7.5 mg/Kg BW/day), or a combination of BPA and DEHP (B+D). Postnatal growth trajectory and intakes were monitored weekly from postnatal weeks 3-12 and daily from weeks 14-16. Female offspring were allowed to reach 14 weeks of age and were then challenged with either a high fat diet (HFD) or normal rat chow for 2 weeks. Body composition and glucose intolerance were measured before the HFD challenge, and after 1 and 2 weeks of HFD treatment. Offspring were sacrificed at week 16, and organs were dissected and weighed. Serum was assayed for insulin and corticosterone levels. Liver cholesterol levels were measured. Results No major changes were seen in female offspring prenatally exposed to BPA or DEHP alone. However, exposure to a combination of B+D induced a postnatal growth retardation that is significant from postnatal week 6 onwards (p=0.014) and a decrease in cumulative food intake (p=0.032) from weeks 3-12 when compared to controls. B+D female offspring had decreased fat (p=0.05), fluid (p=0.0009), and lean (p=0.002) mass at week 14 compared to control groups, impaired fasting glucose tolerance at week 14, significantly higher % gain in fluid (p=0.0008), lean (0.0043), and body weight (p=0.044) from weeks 14-16, and an increase in liver cholesterol levels (p=0.047). These changes were apparent in chow fed, but not HFD-fed animals. No changes were seen in insulin and corticosterone levels between the groups. Conclusion The results indicate that prenatal exposure to B+D altered the postnatal growth trajectory and metabolic profile in female offspring. This suggests a great need to reconsider the possible additive effects of exposure to EDC mixtures during pregnancy.