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Paternal cadmium exposure affects testosterone synthesis by reducing the testicular cholesterol pool in offspring
Jinzhao Zhou1, Yanwei Zhang1, Ling Zeng2
1Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract:
Cadmium（Cd） is a heavy metal that is harmful to human health. Early studies have shown that cadmium can damage testicular structure, affecting testosterone synthesis and spermatogenesis. However, the effect of paternal Cd exposure on the reproductive system of offspring remains unclear. In this study, male 8-week C57BL/6 J mice were used as research objects, and Cd was injected intraperitoneally every other day at a dose of 1 mg/kg for 5 weeks, after which the effect on the reproductive system of offspring male mice was studied. Our results showed that the body weight of the offspring male mice increased faster, with increases of the testicular and epididymis indices under Cd exposure. At the same time, the serum testosterone and free cholesterol decreased, total cholesterol increased, and the sperm concentration decreased. Further qRT-PCR and western blot analyses showed that the expressions of StAR, P450scc, 3β-HSD and 17β-HSD, which are related to testosterone synthesis, was significantly downregulated. Additionally, ATGL, LDLR and SR-BI, which are related to the intracellular cholesterol pool were downregulated, leading to the reduction of the cholesterol pool and the accumulation of lipid droplets. Oil red O and BODIPY staining revealed an increase in the abundance of lipid droplets in testicular tissue of newborn and adult mice. Prediction of tsRNA target genes in the sperm of parents and testicular transcriptome of newborn mice showed that the differentially expressed genes were associated with catabolism of fatty acids, cholesterol and ion channels, while the mitochondrial and lysosome functions of testicular tissue of adult offspring mice were decreased. Overall, our results suggest that paternal Cd exposure reduced the intracellular cholesterol pool of testicular of offspring, affected testosterone synthesis and reproductive system development.
Insights
Paternal exposure to cadmium (Cd) in mice impaired offspring male reproductive systems. This heavy metal exposure reduced testosterone synthesis and altered cholesterol metabolism, impacting testicular development and function.
Area of Science:
- Toxicology
- Reproductive Biology
- Environmental Health
Background:
- Cadmium (Cd) is a toxic heavy metal with known adverse effects on male reproductive health, including testicular damage and impaired spermatogenesis.
- The impact of paternal cadmium exposure on the reproductive system development and function of male offspring remains largely uncharacterized.
Purpose of the Study:
- To investigate the effects of paternal cadmium exposure on the reproductive system of male offspring mice.
- To elucidate the molecular mechanisms underlying cadmium-induced reproductive toxicity in offspring.
Main Methods:
- Male C57BL/6J mice were exposed to cadmium (1 mg/kg) intraperitoneally for 5 weeks.
- Offspring male mice were assessed for reproductive organ indices, serum hormone levels, sperm concentration, and testicular gene/protein expression (qRT-PCR, Western blot).
- Histological analysis (Oil red O, BODIPY staining) and bioinformatic predictions (tsRNA target genes, testicular transcriptome) were performed.
Main Results:
- Paternal cadmium exposure led to increased body weight and reproductive organ indices in offspring male mice.
- Serum testosterone and free cholesterol decreased, while total cholesterol increased, accompanied by reduced sperm concentration.
- Downregulation of key steroidogenic enzymes (StAR, P450scc, 3β-HSD, 17β-HSD) and cholesterol metabolism-related genes (ATGL, LDLR, SR-BI) was observed, alongside increased lipid droplet accumulation in testicular tissue.
- Mitochondrial and lysosomal functions were impaired in adult offspring testes.
Conclusions:
- Paternal cadmium exposure significantly disrupts the reproductive system of male offspring.
- Cadmium exposure reduces the intracellular testicular cholesterol pool, impairs testosterone synthesis, and affects reproductive organ development.
- These findings highlight the transgenerational reproductive risks associated with environmental cadmium exposure.
