Perinatal Exposure to Bisphenol a and High Fat Diets Alter Longitudinal Metabolic Health Via Differential Gene Expression

Presentation Number: FRI 118
Date of Presentation: April 1st, 2016

Elizabeth Hoit Marchlewicz*, Craig Harris and Dana C Dolinoy
University of Michigan School of Public Health, Ann Arbor, MI

Abstract

Prenatal exposure to endocrine disrupting chemicals, like bisphenol A (BPA), may increase risk of metabolic disease across the life course via altered regulation of gene expression. Using an isogenic mouse model, we examined the hypothesis that lifelong metabolic effects of perinatal BPA exposure are exacerbated by a Western high fat diet (HFD) and ameliorated by a Mediterranean HFD. Dams (n=98) were randomized to 1 of 6 diets: control (C), Western (W), Mediterranean (M), or each diet with 50ug BPA/kg chow added, CBPA, WBPA, and MBPA, respectively. Metabolic parameters were assessed at postnatal day 10 (PND10, n=118) and 10 mos. (10M, n=133), with extensive metabolic phenotyping at 2, 4, and 8M. Fatty Liver and Insulin Resistance RT2 Profiler PCR Arrays were run on hepatic RNA from 10M males and females (n=60). ANOVA with Tukey’s post-hoc analysis compared pups’ metabolic outcomes between exposure groups; mixed effects models were used to assess repeated measures over time. At PDN10, CBPA weighed less than C pups (p=0.001); the impact of BPA was negated by both HFDs. Surprisingly, pups exposed to M had higher weekly weights from 5-10M of age (p < 0.001), higher PND10 serum leptin levels (p = 0.003) and greater hepatic triglycerides (p = 0.002), compared to C. No differences were observed with BPA or W diet. Fasting serum insulin at 8M was greater among M females (p=0.026) and males (p=0.047) than controls.

            Hepatic gene expression differences between perinatal exposure groups were more pronounced in 10M female than male offspring and more affected by HFDs than by BPA. In 10M females, W and M diets impacted (p < 0.05) gene expression in the KEGG pathways of fatty acid metabolism, regulation of lipolysis, insulin signaling and resistance and cytokine-cytokine receptor interactions. Interestingly, W females had a greater effect on PPARs, increasing Pparg (p = 0.03) while decreasing Ppargc1a (p = 0.03) and Ppara (p = 0.06) expression, than M females, whose PPAR expression levels did not differ from C. 10M CBPA females had altered expression in similar pathways as HFD, but fewer gene loci were significant. The same patterns of hepatic gene expression were observed in 10M males, but fewer gene loci differences were significant. Thus, perinatal HFD appears to have a greater impact on life course metabolic health than perinatal BPA exposure, and concurrent BPA exposure does not appear to exacerbate effects of either HFD. Sexually dimorphic effects support the need to conduct longitudinal studies in both male and female offspring. Lastly, lipid composition of the HFD matters, resulting in different longitudinal metabolic health outcomes. Shotgun lipidomics on 10M males and females across all six perinatal exposures is currently underway to examine if alterations in fatty acid metabolism and lipolysis gene expression impact circulating lipid levels.

 

Nothing to Disclose: EHM, CH, DCD