Deciphering the ototoxic effects of six organochlorine pesticides on HEI-OC1 cells and mouse cochlear organotypic cultures

Organochlorine pesticides (OCPs), persistent pollutants with mutagenic and carcinogenic risks, that threatens humans, have received limited scientific attention despite their well-documented toxicity. Our study examined the ototoxicity of six prevalent OCPs (p,p’-DDT, p,p’-DDE, p,p’-DDD, Hexachlorocyclohexane, Endosulfan, Heptachlor) that are frequently identified in human biological samples, including blood and breast milk. Our findings revealed that OCPs caused cochlear damage in postnatal day 3 (P3) mice, and exhibited a dose-dependent toxicological response in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells. OCPs exposure led to the generation of ROS (H₂O₂, O₂⁻, mtROS), calcium overload, mitochondrial membrane potential (MMP) decrease, and endoplasmic reticulum (ER) stress activation. Western blot showed a marked reduction in the Bcl-2/Bax ratio, an elevated level of cleaved caspase-9/3, and four increased ER stress markers (p-eIF2α, ATF6, GRP78, CHOP). These results suggest that OCPs induce auditory cell apoptosis through interconnected pathways: oxidative stress, mitochondrial dysfunction, calcium dysregulation, and ER stress. This study provides mechanistic insights into OCP-related ototoxicity, emphasizing the need for stringent regulation of these pervasive environmental toxins.