Long-term and low-dose exposure to TDCPP reduces reproductive capacity by enhancing germline apoptosis associated with activation of DNA damage in Caenorhabditis elegans

Abstract

Tris (1,3-dichloro-2-propyl) phosphate (TDCPP) arouses increasing attention, which probably poses exposure risks to human reproductive health because it is widely used and distributed. Nonetheless, its toxicities to reproductive system remain largely unknown. With Caenorhabditis elegans being the animal model, this study explored reproductive toxicities induced by TDCPP following long-time and low-dose exposure as well as its associated mechanism. According to our findings, brood size and the hatched egg number markedly decreased, meanwhile, relative area and length of gonad arm markedly declined after 0.1-10 μg/L TDCPP exposure. Additionally, 0.1-10 μg/L TDCPP exposure promoted germline apoptosis, down-regulated ced-9 whereas up-regulated ced-3, ced-4, as well as egl-1 levels; additionally, it aggravated germline DNA damage, accompanied by up-regulated clk-2, cep-1, and hus-1 levels. Finally, computational toxicology, including molecular docking and molecular dynamics simulations, showed that TDCPP can effectively embed into the active pockets of CLK-2 and HUS-1 proteins governing DNA damage through interactions such as hydrogen bonds, thereby enhancing the local stability of protein conformation. Consequently, this study illustrated the reproductive toxicities of TDCPP at environmentally relevant concentrations through promoting DNA damage-related germline apoptosis within organisms.