Gestational Low-Dose Bisphenol A Exposure Enhances Susceptibility to Metabolic Disorders in Adult Offspring Mice: Role of the Gut Microbiota-SCFAs-GPRs Axis

Bisphenol A (BPA), frequently detected at low levels in pregnant women, has been linked to long-term metabolic disturbances in offspring. Emerging evidence indicates that maternal gut microbiota critically influence offspring susceptibility to metabolic diseases through their metabolites. This study aimed to investigate how maternal gut microbiota and short-chain fatty acids (SCFAs) mediate the increased susceptibility to high-fat-diet (HFD)-induced metabolic disorders in adult offspring following gestational low-dose BPA exposure. Pregnant mice were exposed to 0, 10, 100, and 1000 nmol/L BPA via drinking water throughout gestation, after which pups were cross-fostered by unexposed dams and fed normal chow or HFD until adulthood. Adult offspring from BPA-exposed dams exhibited aggravated HFD-induced dyslipidemia and insulin resistance. Maternal BPA exposure decreased the abundance of f_Prevotellaceae and g_Bacteroides, accompanied by reduced circulating SCFAs in both dams and offspring. Reduced SCFAs impaired embryonic pancreas and intestinal development by downregulating GPR41 and GPR43, which may predispose offspring to metabolic disorders at adulthood. Importantly, maternal high-fiber diet restored gut microbiota composition along with SCFA production, normalized embryonic GPRs expression, and subsequently alleviated offspring metabolic impairments. These findings provide key insights into BPA-induced developmental programming of metabolic disorders and offer promising strategies against metabolic dysfunction induced by endocrine-disrupting chemicals.