Short Chain Chlorinated Paraffins Impaired Spermatogenesis Process in Mice via Inhibiting α-KG/TET Enzyme Activity.

Area of Science:

• Environmental Science
• Toxicology
• Reproductive Biology

Background:

• Short chain chlorinated paraffins (SCCPs) are environmental contaminants with unclear male reproductive toxicity mechanisms.
• Understanding SCCP toxicity is crucial for human health risk assessment.

Purpose of the Study:

• To investigate the reproductive toxicity of SCCPs in male mice and GC-1 cells.
• To elucidate the molecular mechanisms underlying SCCP-induced male reproductive dysfunction.

Main Methods:

• Utilized male BALB/c mice and GC-1 cells for toxicity studies.
• Assessed α-ketoglutarate (α-KG) levels, TET enzyme activity, and DNA methylation.
• Quantified expression of spermatogenesis-related genes (Rbm46, Sohlh1, Kit, Dmrt1).
• Investigated the role of the TGFβ pathway and oxidative stress in vitro.

Main Results:

• SCCPs reduced α-KG content in testicular cells, inhibiting TET enzyme activity and increasing genome-wide methylation.
• SCCPs significantly decreased promoter demethylation and expression of key spermatogenesis genes.
• SCCP exposure impaired spermatogonia-to-spermatocyte transformation and reduced sperm quality.
• In vitro studies indicated TGFβ pathway activation via oxidative stress contributes to α-KG reduction.

Conclusions:

• SCCPs induce male reproductive toxicity through a novel metabolic pathway involving α-KG reduction and impaired spermatogenesis gene regulation.
• This study provides a theoretical basis for preventing SCCP reproductive toxicity.