Gestational exposure to TDCIPP disrupts embryonic development via LEPR-mediated IL6/JAK2/STAT3 signaling pathway in mice

Abstract

Organophosphate esters (OPEs) are widely used flame retardants that have become ubiquitous in the environment. As typical environmental endocrine disruptors (EEDs), their adverse effects on human reproduction and development have raised global concern. In this study, we assessed the embryotoxicity of tris (1,3-dichloro-2-propyl) phosphate (TDCIPP, the most frequently detected OPEs in environment and human) and illustrated the molecular mechanisms in mouse embryos in vivo and in vitro. We found that exposure to 1 mg/kg⋅bw/day TDCIPP from gestational day (GD) 1 to GD14 significantly induced embryonic absorption and deformity in pregnant mice. Similar embryonic absorption and deformity were observed in in vitro fertilization (IVF) mice model after TDCIPP-treated embryos were transferred. Mechanistically, we found that exposure to TDCIPP downregulated the expression of leptin receptor (LEPR) and inhibited the downstream signaling pathway of interleukin 6 (IL6) /janus kinase 2 (JAK2) /signal transducer and activator of the transcription 3 (STAT3). In embryo culture system, the supplementation of 100 ng/mL IL6 or 50 ng/mL IL10 markedly alleviated TDCIPP-induced embryonic absorption and deformity. Collectively, our results suggest that the inhibition of LEPR-mediated IL6/JAK2/STAT3 signaling pathway might play a role in TDCIPP-induced embryotoxicity.