Short\nChain Chlorinated\nParaffins Impaired Spermatogenesis\nProcess in Mice via Inhibiting α‑KG/TET Enzyme Activity

Short chain chlorinated paraffins\n(SCCPs) are widely\nfound in various\nenvironmental media and potentially threaten human health. However,\nthe toxicity mechanisms of SCCPs to the male reproductive system remain\nunclear. In this study, male BALB/c mice and GC-1 cells were used\nto investigate the reproductive toxicity of SCCPs and their molecular\nmechanisms. SCCPs decreased the content of the tricarboxylic acid\ncycle intermediate α-KG in testicular cells, thus inhibiting\nthe activity of the DNA demethylase TET enzyme and resulting in an\nincrease in the overall methylation level of the testicular genome.\nCorrespondingly, the promoter demethylation and expression of spermatogenesis-related\ngenes <i>Rbm46</i>, <i>Sohlh1</i>, <i>Kit</i>, and <i>Dmrt1</i> were significantly reduced by SCCPs,\nwhich further prevented the transformation of spermatogonia to spermatocytes\nand reduced sperm quality in mice. The <i>in vitro</i> experiments\nsuggested that the TGFβ pathway activated by oxidative stress\nmight be an essential reason for inhibiting the tricarboxylic acid\ncycle and the reduction of α-KG content in testicular cells\ninduced by SCCPs. Overall, this study reveals a novel metabolic regulatory\nmechanism of SCCPs-induced spermatogenesis disorders, which provides\nan essential theoretical basis for the prevention of reproductive\ntoxicity of SCCPs.