Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) associated with non-alcoholic fatty liver disease (NAFLD). The effects of gestational BPA exposure on hepatic lipid accumulation in offspring are not fully understood. Here, we investigate the sex-dependent effects of gestational BPA exposure on hepatic lipid and glucose metabolism in the offspring of mice to reveal the mechanisms underlying gestational BPA exposure-associated NAFLD. Pregnant mice were administered gavage with or without 1 μg kg−1 day−1 BPA at embryonic day 7.5 (E7.5)–E16.5. Hepatic glucose and lipid metabolism were evaluated in these models. Both male and female offspring mice exhibited hepatic fatty liver after BPA treatment. Lipid accumulation and dysfunction of glucose metabolism were observed in male offspring. We revealed abnormal expression of lipid regulators in the liver and that inhibition of peroxisome proliferator-activated receptor γ (PPARγ) repressed hepatic lipid accumulation induced by gestational BPA exposure. We also found a sex-dependent decrease of hepatocyte nuclear factor 1b (HNF1b) expression in male offspring. The transcriptional repression of PPARγ by HNF1b was confirmed in L02 cells. Downregulation of HNF1b, upregulation of PPARγ, and subsequent upregulation of hepatic lipid accumulation were essential for NAFLD development in male offspring gestationally exposed to BPA as well as BPA-exposed adult male mice. Dysregulation of the HNF1b/PPARγ pathway may be involved in gestational BPA exposure-induced NAFLD in male offspring. These data provide new insights into the mechanism of gestational BPA exposure-associated sex-dependent glucose and lipid metabolic dysfunction.

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β‑cell dysfunction is the primary cause of type 2 diabetes mellitus (T2DM). 1,2‑dicarbonyl compounds, such as 3‑deoxyglucosone (3DG) have been reported to increase the risk of T2DM. Abnormal elevation of plasma 3DG may impair β‑cell function and thereby, it is linked to T2DM. Previous findings suggest that exogenous 3DG may serve an important role in the development of pre‑diabetes. In the present study, the authors examine whether exogenous 3DG induces impaired glucose regulation in mice by decreasing β‑cell function involving of accumulation of plasma 3DG. At two weeks following administration of 3DG, fasting blood glucose (FBG) levels, oral glucose tolerance (by a glucose meter) and plasma levels of 3DG (by HPLC) and insulin (by radioimmunoassay) were measured. Glucose‑stimulated insulin secretion in cultured pancreas islets and INS‑1 cells was measured by radioimmunoassay. Western blotting was used to examine the expression of the key molecules of the insulin‑PI3K signaling pathway. 3DG treatment increased FBG and fasting blood insulin levels, reduced oral glucose tolerance in conjunction with decreased ∆Ins30‑0/∆G30‑0. In 3DG‑treated mice, an increase in the plasma 3DG level was observed, which was most likely the mechanism for decreased β‑cell function. This idea was further supported by these results that non‑cytotoxic 3DG concentration obviously decreased glucose‑stimulated insulin secretion in cultured pancreas islets and INS‑1 cells exposure to high glucose (25.5 mM). 3DG decreased the expression of GLUT2 and phosphorylation of IRS‑1, PI3K‑p85 and Akt in high glucose‑induced INS‑1 cells. To the best of the authors' knowledge, the present study is the first to demonstrate that exogenous 3DG induced normal mice to develop IGR, resulting from β‑cell dysfunction. Exogenous 3DG administration increased plasma 3DG levels, which participates in inducing β‑cell dysfunction, at least in part, through impairing IRS‑1/PI3K/GLUT2 signaling.