EHDPP impairs intestinal microbiota homeostasis and induces placental injury through choline mediated gut-placenta axis

2-Ethylhexyl-diphenyl phosphate (EHDPP) is an organophosphate ester (OPE) with roles of flame retardant and plasticizer. It is widely used in various applications, detected in environmental matrices and human body, threatening ecological environment and human health. Some OPEs have been reported to disturb the gut microbiota, the gut microbiota mediates placental function. Our previous study showed EHDPP causes placental toxicity and fetal weight loss, it is unknown that whether EHDPP affects fetal development through the gut-placenta axis and whether it is feasible to fight against EHDPP induced placental toxicity through the gut-placenta axis. Our study investigates and indicates that EHDPP disrupts normal gut function by disturbing the gut microbiota homeostasis and compromising the intestinal barrier integrity. The disruption of EHDPP leads to reduced choline transporter expression of the solute carrier family 44A2 (SLC44A2), impaired choline absorption and distribution in placenta. Gut microbiota depletion increases the choline level in placenta. Both gut microbiota depletion and choline supplementation alleviate the EHDPP induced fetal weight loss by increasing the expression and activation of LXRα. In addition, a mendelian randomization study indicates that choline transporter SLC44A2 expression reduction significantly increased the risk of low birth weight in human. In summary, EHDPP exposure exacerbates placental and fetal damage through attenuating the beneficial function of choline mediated gut-placental axis. Direct choline supplementation or indirect choline level upregulation by gut microbiota depletion are therapeutic strategies for EHDPP induced placental injury.