Host: The Japanese Society of Toxicology
Name : The 51st Annual Meeting of the Japanese Society of Toxicology
Date : July 03, 2024 - July 05, 2024
Chlorinated paraffins (CPs) are mixtures of linear chloroalkanes classified by length into short-, medium-, and long-chain CPs (SCCPs, MCCPs, and LCCPs), with various chlorination degrees, extensively used as high-pressure lubricants and additives. CPs high exposure levels and maternal-foetal transfer elicit alarming human health risks. To elucidate the early human developmental toxicity of CPs, an in vitro model based on undifferentiated human pluripotent stem cells (iPSCs) was validated and used for the investigation of SCCPs (63% Cl), MCCPs (57% Cl), and LCCPs (49% Cl) cytotoxicity, oxidative stress induction potency, and aptitude to alter the expression levels of genes related to metabolism (CYPs: 1A1, 1A2, 1B1, 3A4, and 4A11) and DNA repair systems (REV3L, RAD54L, RAD54B, KU70, and KU80). The three CPs displayed a low non-monotonic cytotoxicity and an inability to induce oxidative stress. Interestingly, the mRNA expression levels of all investigated CYPs were inhibited after 48 hours exposure, suggesting the transactivation inhibition of their regulatory nuclear receptors. Furthermore, SCCPs disturbed the mRNA expression levels of REV3L, RAD54L, RAD54B, and KU70, evoking their carcinogenicity, while MCCPs downregulated REV3L and RAD54B expression, uncovering a concerning effect, and LCCPs were inactive. In conclusion, our results suggest that the toxic effects of CPs are cell-dependent, with low potency for cytotoxicity, yet high potency for metabolic inhibition and DNA integrity alteration (particularly SCCPs) during the early stages of human development.
