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Published on: December 28, 2021
Short Chain Chlorinated Paraffins Impaired Spermatogenesis Process in Mice via Inhibiting α-KG/TET Enzyme Activity
Ruiyang Meng1, Xingde Du1, Yu Fu1
1College of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, China.
Abstract:
Short chain chlorinated paraffins (SCCPs) are widely found in various environmental media and potentially threaten human health. However, the toxicity mechanisms of SCCPs to the male reproductive system remain unclear. In this study, male BALB/c mice and GC-1 cells were used to investigate the reproductive toxicity of SCCPs and their molecular mechanisms. SCCPs decreased the content of the tricarboxylic acid cycle intermediate α-KG in testicular cells, thus inhibiting the activity of the DNA demethylase TET enzyme and resulting in an increase in the overall methylation level of the testicular genome. Correspondingly, the promoter demethylation and expression of spermatogenesis-related genes Rbm46, Sohlh1, Kit, and Dmrt1 were significantly reduced by SCCPs, which further prevented the transformation of spermatogonia to spermatocytes and reduced sperm quality in mice. The in vitro experiments suggested that the TGFβ pathway activated by oxidative stress might be an essential reason for inhibiting the tricarboxylic acid cycle and the reduction of α-KG content in testicular cells induced by SCCPs. Overall, this study reveals a novel metabolic regulatory mechanism of SCCPs-induced spermatogenesis disorders, which provides an essential theoretical basis for the prevention of reproductive toxicity of SCCPs.
Insights
Short chain chlorinated paraffins (SCCPs) disrupt male fertility by lowering α-KG levels, inhibiting DNA demethylase TET enzymes, and reducing key spermatogenesis gene expression, impacting sperm quality.
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.
