Genetic Background in the Rat Impacts Metabolic Outcomes of Post‐wean BPF Exposure
Authors: Wagner Valerie A. , Clark Karen C. , Holl Katie L. , Reho John J. , Solberg Woods Leah C. , Lehmler Hans‐Joachim , Grobe Justin L. , Kwitek Anne E. 
Published: May 2022

Bisphenol F (BPF) is a common substitute for bisphenol A (BPA), an endocrine disruptor associated with cardiometabolic disease, and is found in polycarbonates and consumer products. BPF is a potent endocrine disruptor with effects on thyroid, reproductive health, and neuroendocrine functions. Interindividual variation in human bisphenol levels suggests that gene x environment (GxE) interactions influence cardiometabolic disease risk from bisphenol exposure. Traditional in vivo toxicity studies are performed in isogenic or genetically undefined outbred rodents, leading to conflicting results possibly due to GxE interactions. This limitation can be avoided by studying the N/NIH Heterogeneous Stock (HS) rats, an outbred population derived from 8 founder inbred strains that are readily amenable to genetic study.

Our overall study hypothesis is that BPF‐induced cardiometabolic disease has underlying genetic risk, which can be identified using the HS rat and its founding inbred strains. We previously demonstrated that 5 weeks of post‐wean BPF exposure significantly impacts body growth and adiposity in male HS rats. The goal of this project was to evaluate the metabolic impact of post‐wean BPF exposure in a subset of HS founding inbred strains. Weanling littermate pairs of male and female ACI/EurMcwi (ACI), BN/NHsdMcwi (BN), F344/Stm (F344), and WKY/NCrl (WKY) rats were randomly exposed to either vehicle (0.1% EtOH) or 1.125 mg BPF/L in 0.1% EtOH for 10 weeks in drinking water. Cardiometabolic measures, tissues, urine, and feces were taken.

Females

Feeding efficiency was significantly increased in BPF ACI females compared to vehicle ACI females. BN, F344, and WKY females showed no impact from BPF exposure.

Males

Digestive efficiency was decreased in BPF ACI males compared to all other males. BPF F344 males showed a trend in decreased body length compared to vehicle F344 males. Preliminary metabolic rate measures indicate that BPF ACI and F344 males have decreased metabolic rates compared to vehicle exposed males of the same strain. BPF‐exposed male endocrine glands were affected compared to vehicle males of the same strain: ACI males had increased thyroid gland mass, BN males showed a trend in increased pituitary gland and testes mass, and WKY males had increased adrenal gland mass. Analysis of pituitary‐secreted hormones suggests disruption of the hypothalamic‐pituitary‐gonadal (HPG) and ‐adrenal (HPA) axis in BPF WKY males and the HPG axis in BPF ACI males compared to vehicle males of the same strain.

Our preliminary data suggest that post‐wean BPF exposure has numerous effects on the endocrine system and metabolic rate depending on genetic background. The unique outcomes seen in these strains exemplifies that HS rat founding inbred strains possess diverse bisphenol‐exposure risk alleles influencing metabolic health. 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.