High doses of bisphenol AF (BPAF), a widely used chemical in many products, has been reported to exert adverse effects on lipid or glucose metabolism, but whether low-dose exposure, especially in combination with a high-sugar, high-fat diet (Western diet, WD), has unacceptable effects remains unexplored. Here, we investigated the effects of postnatal exposure to 50 μg/kg/d (low) BPAF on glycolipid homeostasis in mice receiving administration through drinking water under the WD stress after weaning or not, in comparison with the effects 5000 (high) BPAF without stress. After approximately 8-week exposure, blood tests of glucose metabolism revealed that high-dose BPAF caused insulin resistance and elevated insulin levels in a normal diet (ND)-fed mice
low-dose BPAF exerted slight effects in ND-fed mice but caused significant glucose metabolic impairment under the WD stress. Also, low-dose BPAF exerted limited effects on pancreas islets as well as hepatic histology and metabolic homeostasis in ND-fed mice, but aggravated pancreatic and hepatic impairments caused by the WD stress. We also conducted cell culture experiments using β-TC-6 and HepG2 cells to explore whether BPAF could directly interfere with pancreatic cells and hepatocytes. In vitro assays showed that BPAF affected insulin secretion of pancreatic β-TC-6 cells in a glucose-dependent manner and glucose sensitivity of HepG2 cells, with slight effects on lipid metabolism in HepG2 cells. All results collectively demonstrate that low-dose BPAF caused metabolic disorders under the WD stress, highlighting its health risks. Besides, in vitro data suggest that BPAF may directly affect glucose metabolism rather than lipid metabolism.