Maternal Exposure to Bisphenol A Bis(diphenyl Phosphate) Induces Offspring Colitis through Disrupting the Gut Microbiome-Metabolite Axis

Bisphenol-A bis(diphenyl phosphate) (BDP) has been detected in biological organisms, but its toxicological effects remain unclear. In this study of 4376 participants, the characteristic BDP metabolite diphenyl phosphate was associated with gastrointestinal diseases via a nonlinear dose–response relationship, and was identified as a risk factor (OR = 1.02; 95% CI: 1.01–1.04; P = 0.013). Pregnant rats received 50 mg/kg/day BDP during gestation (GD 14–20) or gestation plus lactation (GD 14–PND 35). Both regimens triggered colonic inflammation and gut microbiome dysbiosis in offspring. The combined exposure group showed more severe effects, including persistent histopathological damage, elevated Il-1 β and Il-6, and reduced microbial diversity. LC-MS/MS and 16S rRNA sequencing were used to assess BDP distribution and gut microbiome alterations. BDP crossed the placental barrier. SourceTracker analysis confirmed maternal microbiome transmission as the primary source (>70%) of offspring gut microbiome, accompanied by Streptococcus enrichment and Bifidobacterium depletion. Metabolite-inflammation network analysis showed positive correlations of butyrate and negative correlations of propionate with proinflammatory cytokines ( IL-1 β, IL-6, and TNF- α), which were subsequently confirmed by in vitro experiments. These findings demonstrate a transgenerational mechanism whereby prenatal BDP exposure induces offspring colonic inflammation via the gut microbiome–metabolite axis, informing maternal-infant intervention strategies.