Effects of Low-Dose Developmental Bisphenol A Exposure on Metabolic Parameters and Gene Expression in Male and Female Fischer 344 Rat Offspring

Abstract

Background:Bisphenol A (BPA) is an endocrine-disrupting chemical that may contribute to development of obesity and metabolic disorders. Humans are constantly exposed to low concentrations of BPA, and studies support that the developmental period is particularly sensitive.Objectives:The aim was to investigate the effects of low-dose developmental BPA exposure on metabolic parameters in male and female Fischer 344 (F344) rat offspring.Methods:Pregnant F344 rats were exposed to BPA via their drinking water, corresponding to 0.5μg/kg BW/d (BPA0.5; n=21) or 50μg/kg BW/d (BPA50; n=16), from gestational day (GD) 3.5 until postnatal day (PND) 22, and controls were given vehicle (n=26). Body weight (BW), adipose tissue, liver (weight, histology, and gene expression), heart weight, and lipid profile were investigated in the 5-wk-old offspring.Results:Males and females exhibited differential susceptibility to the different doses of BPA. Developmental BPA exposure increased plasma triglyceride levels (0.81±0.10 mmol/L compared with 0.57±0.03 mmol/L, females BPA50 p=0.04; 0.81±0.05 mmol/L compared with 0.61±0.04 mmol/L, males BPA0.5 p=0.005) in F344 rat offspring compared with controls. BPA exposure also increased adipocyte cell density by 122% in inguinal white adipose tissue (iWAT) of female offspring exposed to BPA0.5 compared with controls (68.2±4.4 number of adipocytes/HPF compared with 55.9±1.5 number of adipocytes/HPF; p=0.03) and by 123% in BPA0.5 females compared with BPA50 animals (68.2±4.4 number of adipocytes/high power field (HPF) compared with 55.3±2.9 number of adipocytes/HPF; p=0.04). In iWAT of male offspring, adipocyte cell density was increased by 129% in BPA50-exposed animals compared with BPA0.5-exposed animals (69.9±5.1 number of adipocytes/HPF compared with 54.0±3.4 number of adipocytes/HPF; p=0.03). Furthermore, the expression of genes involved in lipid and adipocyte homeostasis was significantly different between exposed animals and controls depending on the tissue, dose, and sex.Conclusions:Developmental exposure to 0.5μg/kg BW/d of BPA, which is 8–10 times lower than the current preliminary EFSA (European Food Safety Authority) tolerable daily intake (TDI) of 4μg/kg BW/d and is within the range of environmentally relevant levels, was associated with sex-specific differences in the expression of genes in adipose tissue plasma triglyceride levels in males and adipocyte cell density in females when F344 rat offspring of dams exposed to BPA at 0.5μg/kg BW/d were compared with the offspring of unexposed controls. https://doi.org/10.1289/EHP505

Prenatal Bisphenol A Exposure is Linked to Epigenetic Changes in Glutamate Receptor Subunit Gene Grin2b in Female Rats and Humans

“…Animal housing and treatment are described elsewhere 58 , 59 . Briefly, female F344/DuCrl rats (Charles River) arrived at 7 weeks of age and were randomly distributed into three dosing groups (vehicle, 0.5 or 50 μg BPA/kg BW/d) and exposed to BPA via their drinking water, corresponding to approximately 0.5 or 50 μg/kg bw/day or vehicle control from gestational day 3.5 until weaning (postnatal day 21) using BPA (Sigma Aldrich, Missouri, USA, CAS 80-05-7) with ≥99% purity dissolved in ethanol (1% of final solution).…”

In vivoandin vitrobisphenol A exposure effects on adiposity

“…Although the sex-specific effects of BPA are well documented including the differential susceptibility of males and females to different doses of BPA 47,[81][82][83][84][85] , the underlying mechanism remains unclear. 82 The plausible explanation may involve sex hormones, genomic and non-genomic pathway involving nuclear estrogen receptors, differing developmental pattern and/or epigenetic influence. 47,83,86…”

An Untargeted Metabolomics Approach to Investigate the Metabolic Modulations of HepG2 Cells Exposed to Low Doses of Bisphenol A and 17β-Estradiol

“…Then, we used bioinformatics (Metabolic Network modeling) methods to further investigate the biological pathways modulated by these estrogens: E2 as the reference hormone, and BPA as a model xeno-estrogen with well-documented endocrine disrupting properties, but also strongly suspected metabolic effects. Many EDCs with xeno-estrogenic properties can act as metabolic modulators ( 1 , 33 , 34 ). We previously demonstrated metabolic changes in the liver and brain of mice exposed during intra-utero development and lactation, to low doses of BPA ( 10 ).…”