A comprehensive atlas of multi-tissue metabolome and microbiome shifts: Exploring obesity and insulin resistance induced by perinatal bisphenol S exposure in high-fat diet-fed offspring

Bisphenol S (BPS) is widely used as a substitute for Bisphenol A (BPA). While perinatal BPS exposure is suspected to increase susceptibility to high-caloric diet-induced adipogenesis, how BPS affects offspring remains largely unknown. This study explored effects of prenatal BPS exposure on adiposity and insulin resistance in high-fat diet (HFD)-fed C57BL/6 offspring, revealing significant changes in body weight, glucose tolerance, insulin sensitivity, and histopathology. Employing nontargeted metabolomics and 16S rRNA sequencing, we constructed a comprehensive atlas of metabolome and microbiome shifts across heart, liver, pancreas, white adipose tissue (WAT), brown adipose tissue (BAT), and feces. Male offspring showed greater metabolic and microbial disturbances. Low-dose BPS exposure (0.05 mg/kg/d) induced changes across entire atlas comparable to high-dose (5 mg/kg/d). BAT and WAT were key target tissues with the most significant metabolic disturbances. BPS disrupted fatty acid β-oxidation in WAT by reducing carnitine carriers, causing WAT fat accumulation. A resistance mechanism to BPS exposure was indicated by both mobilization of BAT compensatory thermogenesis, characterized by increased carnitines and UCP1 expression, and an increase in beneficial commensal bacteria. Their competition and imbalance contributed to obesity and insulin resistance in offspring, highlighting the potential for early interventions targeting key metabolites and microbiota.