Impacts of Di(2-Ethylhexyl) Terephthalate on Multigenerational Fitness of Caenorhabditis elegans via Lipid Metabolism and Neural Regulation

Abstract

Di(2-ethylhexyl) terephthalate (DEHTP) is a substitutive plasticizer with wide occurrence in environmental and human samples and therefore its toxicity is urging concerns. Presently, its effects on the fitness of Caenorhabditis elegans (i.e., reproduction, lifespan, and behavior) were explored with a consecutive exposure over four generations (F1–F4). At mg/L and μg/L levels, DEHTP stimulated reproduction in F1 and F3 (e.g., 35% and 28% higher than the control at 8.0 mg/L) while inhibiting it in F2 and F4 (e.g., 22% and 18% less than the control at 8.0 mg/L), representing oscillation over generations. Meanwhile, DEHTP inhibited lifespan in F1 and F3 while stimulating it in F2 and F4, showing trade-off relationships with reproductive influences. Regarding behavior, DEHTP inhibited satiety quiescence duration, body bending, and head swing, while stimulating reverse and omega turns. In mechanism exploration, DEHTP disturbed lipid metabolites and lipid metabolism enzymes. Moreover, the effects on reproduction showed positive correlations with those on fatty acid synthase (FAS) and acyl-CoA (FA-CoA). DEHTP also disturbed neural regulations including neural transmitters and the expressions of related genes. Out of expectation, the effects on neural regulations were positively correlated with those on lipid metabolism, but not with locomotion behavior. Hierarchical clustering analysis (HCA) showed that serotonin was more connected with neural regulations than other indicators in F1 and F3, while it was more connected with behavior than others in F2 and F4. The HCA results also supported the oscillatory changes in effects of DEHTP over generations.