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

Environ Health Perspect. 2017 Jun 28;125(6):067018. doi: 10.1289/EHP505.


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 0.5 μg/kg BW/d (BPA0.5; <em>n</em>=21) or 50 μg/kg BW/d (BPA50; <em>n</em>=16), from gestational day (GD) 3.5 until postnatal day (PND) 22, and controls were given vehicle (<em>n</em>=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&plusmn;0.10 mmol/L compared with 0.57&plusmn;0.03 mmol/L, females BPA50 <em>p</em>=0.04; 0.81&plusmn;0.05 mmol/L compared with 0.61&plusmn;0.04 mmol/L, males BPA0.5 <em>p</em>=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&plusmn;4.4 number of adipocytes/HPF compared with 55.9&plusmn;1.5 number of adipocytes/HPF; <em>p</em>=0.03) and by 123% in BPA0.5 females compared with BPA50 animals (68.2&plusmn;4.4 number of adipocytes/high power field (HPF) compared with 55.3&plusmn;2.9 number of adipocytes/HPF; <em>p</em>=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&plusmn;5.1 number of adipocytes/HPF compared with 54.0&plusmn;3.4 number of adipocytes/HPF; <em>p</em>=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 0.5 μg/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 4 μg/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 0.5 μg/kg BW/d were compared with the offspring of unexposed controls. https://doi.org/10.1289/EHP505.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Benzhydryl Compounds / metabolism
  • Benzhydryl Compounds / toxicity*
  • Dose-Response Relationship, Drug
  • Endocrine Disruptors / metabolism
  • Endocrine Disruptors / toxicity*
  • Female
  • Gene Expression / drug effects
  • Liver / metabolism
  • Male
  • Phenols / metabolism
  • Phenols / toxicity*
  • Rats
  • Rats, Inbred F344


  • Benzhydryl Compounds
  • Endocrine Disruptors
  • Phenols
  • bisphenol A