Peripheral T3 signaling is target of pesticides in zebrafish larvae and adult liver.

The intra-tissue level of thyroid hormones (THs) regulates organ functions. Environmental factors can impair it by damaging the thyroid gland and/or the peripheral TH metabolism. We investigated the effects of embryonic and/or long-life exposure to low-dose pesticides, ethylenethiourea (ETU), chlorpyrifos (CPF) and their mixture, on the intra-tissue T4/T3 metabolism/signalling in zebrafish at different life stages. Hypothyroidism was evidenced in exposed larvae that showed reduced number of follicle and induced tshb mRNAs. Despite that, we evidenced the increase of free T4 (fT4) and free T3 (fT3) levels/signalling that was confirmed by the transcriptional regulation of TH metabolic enzymes (deiodinases) and T3-regulated mRNAs (cpt1, igfbp1a). The second-generation larvae showed effects on thyroid and TH signalling even when not directly exposed, suggesting a role of the parental exposure. In adult zebrafish we found a sex-dependent damage of hepatic T3 level/signalling associated to liver steatosis, more pronounced in female, with a sex-dependent alteration of transcripts codifying the key enzymes involved in “de novo lipogenesis” and of β- oxidation. We found an impaired activation of liver T3 and PPARα/Foxo3a pathways whose deregulation was already involved in mammalian liver steatosis. The data underscore the intra-tissue imbalance of T3 level as a target of thyroid endocrine disruptors (THDC) and suggest that the effects of slight modification of T3 signalling might be amplified by its direct regulation or crosstalk with PPAR/Foxo3a pathways. Because T3 levels define the hypothyroid/hyperthyroid status of each organ, our findings might explain the pleiotropic and site-dependent effects of pesticides.