Environmental exposure to endocrine disruptors induces insulin resistance and hepatic inflammation in adult male rats, with partial transmission across subsequent generations.

Animal models relying on realistic exposure scenario that can substantiate the role of endocrine disruptors (EDs) in the incidence of metabolic diseases are currently lacking. In this study, we developed a toxicological rat model using a mixture of three prominent EDs (bisphenol S, methylparaben, triclosan), administered at low (LD) or high doses (HD), based on data from human cohorts. Direct effects were examined in the F0 generation, where male rats were exposed to the ED mixture at the gamete stage, in utero and via drinking water from weaning until 19 weeks of age. Multi- and transgenerational transmission of ED effects were then investigated in the non-directly exposed F1 and F3 generations. As a major ED-induced phenotype, male F0 HD rats developed marked insulin resistance, which was associated with increased fasting insulinemia and liver inflammation characterized by the presence of lymphocyte infiltrates. This phenotype was partially transmitted to F1 HD rats and, to a much lesser extent, to F3 HD rats. The severity of this phenotype was related to the differential expression of multiple key genes involved in insulin resistance. It was also associated with decreased kinome activity, including many protein kinases involved in inflammatory and insulin signaling. These findings support epidemiological data and raise further concerns about the delayed effects of EDs.