Bile acids and tryptophan metabolism are novel pathways involved in metabolic abnormalities in BPA-exposed pregnant mice and male offspring.
Endocrinology. 2017 May 25. Epub 2017 May 25. PMID: 28549143
Increasing evidence has demonstrated that exposure to endocrine disrupting chemicals (EDCs) impacts maternal and fetal health, but the underlying mechanisms are still unclear. We have previously shown that dietary exposure to 10µg/kg bw/day and 10 mg/kg bw/day bisphenol A (BPA) during pregnancy induced metabolic abnormalities in F1 male offspring and gestational glucose intolerance in F0 pregnant mice. The aim of this study is to elucidate the underlying etiologies of BPA exposure-induced metabolic disease by analyzing male fetal liver metabolome. Using the Metabolon Discover HD4 Platform, our laboratory has identified metabolic pathways that are altered by BPA exposure including biochemicals in lipid and amino acid metabolism. Specifically, primary and secondary bile acids were increased in liver from BPA-exposed embryonic day (E) 18.5 male fetuses. We subsequently showed that increased bile acid was associated with defective Fxr- dependent negative feedback mechanism in BPA exposed-fetuses. Additionally, through metabolomics, we observed that BPA-exposed fetuses had elevated tryptophan levels. Independent liquid chromatography and mass spectrometry (LC-MS) measurement revealed that BPA-exposed dams also had increased tryptophan relative to controls. Because several key enzymes in tryptophan catabolism are vitamin B6-dependent and vitamin B6 deficiencies have been previously linked to gestational diabetes, we tested the impact of vitamin B6 supplementation and showed that it rescued gestational glucose intolerance in BPA-exposed pregnant mice. Our study has therefore identified two novel pathways (bile acid and tryptophan metabolism) that potentially underlie BPA-induced maternal and fetal metabolic disease.