Metabolic Effects of Maternal Bisphenol F Exposure in Population-based Heterogeneous Stock Rats

Bisphenol F (BPF) is marketed as a ‘safe’ substitute for bisphenol A (BPA), a risk factor for obesity and heart disease, in manufacturing polycarbonates and in common consumer products. BPF’s environmental presence is growing rapidly and is detected in 66.5% of U.S. adults. There is evidence of individual variation in bisphenol levels, suggesting that gene x environment (GxE) interactions influence risk of cardiometabolic disease from bisphenol exposure. Few studies of BPF exposure in either humans or animals have been performed, thus their associated health risks are mostly unknown. Traditional in vivo toxicity studies are performed in genetically undefined outbred rats or genetically homogeneous inbred mice, leading to conflicting results possibly due to GxE interactions. The N/NIH Heterogeneous Stock (HS) rats are outbred rats that better model humans yet are amenable to genetic study. Our overall hypothesis is that BPF exposure is a cardiometabolic disease risk factor based on underlying genetic susceptibility, which can be identified using the HS rat model. We previously demonstrated that five weeks of post-wean BPF exposure significantly impacts body growth and adiposity in male HS rats. The goal of this project was to determine if maternal BPF exposure also influences growth and adiposity in HS rats, since maternal exposure to BPA is known to impact the metabolic health of both the mother and offspring. HS female breeders were randomly selected for exposure to either vehicle (0.1% Ethanol), 0.1125 mg/L BPF in 0.1% Ethanol (Low Dose), or 1.125 mg/L BPF in 0.1% Ethanol (High Dose) in drinking water during gestation and lactation (~6 weeks total exposure time). One pup of each sex was weaned at 3 weeks of age with no additional exposure. Tissues were taken from dams. Weight and adiposity measures were obtained from weanlings until 8 weeks of age. Our study determined that dams exposed to High Dose showed significantly increased gonadal white adipose tissue (GWAT) mass and trended increased brown adipose tissue (BAT) mass (Table 1). Maternal High Dose exposure impacted weanling body composition at 7 weeks of age as measured by nuclear magnetic resonance (NMR), with the female weanlings significantly increasing %fat mass and trending decreased %lean mass. Maternal BPF exposure also impacted weanling BAT mass, with High Dose female weanlings trending increased BAT mass. No differences were found in male offspring. Our preliminary data suggest that maternal BPF exposure alters adiposity of both the HS dams and female offspring. This work supports BPF exposure as a cardiometabolic disease risk factor and indicates that the HS rat will be a useful model for dissecting GxBPF interactions on metabolic health. Support or Funding Information NIH P30 ES005605, National Institutes of Health Predoctoral Training Grant T32GM008629 Subject Phenotype Vehicle Low Dose High Dose Dam %%Vehicle n = 10, Low Dose n = 9, High Dose n = 5 BAT (mg) 313 ± 14 343 ± 20 370 ± 31 GWAT (g) 5.7 ± 0.4 5.3 ± 0.5 7.9 ± 0.8 **p < 0.05 High Dose vs Vehicle (linear mixed model regression, Likelihood Ratio Test) Female Weanling ##Vehicle n = 10, Low Dose n = 10, High Dose n = 8 (NMR Vehicle n = 8, Low Dose n = 6, High Dose n = 4) Fat % 9.9 ± 1.1 14.0 ± 2.9 17.0 ± 2.0 **p < 0.05 High Dose vs Vehicle (linear mixed model regression, Likelihood Ratio Test) Lean % 73.0 ± 1.1 69.3 ± 2.6 66.4 ± 1.7 BAT (mg) 175 ± 9 180 ± 10 213.8 ± 23 Values: mean ± SEM %Vehicle n = 10, Low Dose n = 9, High Dose n = 5 #Vehicle n = 10, Low Dose n = 10, High Dose n = 8 (NMR Vehicle n = 8, Low Dose n = 6, High Dose n = 4) *p < 0.05 High Dose vs Vehicle (linear mixed model regression, Likelihood Ratio Test)