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Adolescent exposure to organophosphate insecticide malathion induces spermatogenesis dysfunction in mice by
Shouchun Xiao1, Jingna Cui1, Yue Cao1
1Beijing Advanced Innovation Centre for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, No.2 West Yuanmingyuan Road, Beijing, 100193, PR China.
Abstract:
Chemical-caused reproductive dysfunction has emerged as a global public health concern. This study investigated the adverse effects of the organophosphorus pesticide malathion on reproductive function in adolescent male mice at environmentally relevant concentrations. The results indicated that eight-week malathion exposure reduced testis weight, caused sex and thyroid hormone disorders, and induced testicular spermatogenic epithelium damage and oxidative stress. Testicular RNA sequencing indicated that malathion significantly affected testicular energy metabolism, hypoxia-inducible factor 1 (HIF-1) signaling, and steroid hormone biosynthesis pathways. Malathion significantly increased the gene and protein expression of HIF-1α by upregulating key genes in the mitogen-activated protein kinase (MAPK) pathway (Map2k2, Mapk3, and Eif4e2) and the phosphatidylinositol 3-kinase (PI3K) pathway (Pik3r2 and Akt1). Furthermore, malathion downregulated HIF-1α degradation-regulating genes while upregulating anaerobic metabolism and inflammation-related genes, thereby inhibiting normoxia and promoting hypoxia processes. Testicular hypoxia subsequently induced steroid hormone biosynthesis disorders and spermatogenesis dysfunction. Molecular docking verified that malathion interfered with HIF-1α and steroid hormone synthases (CYP11A1, CYP17A1 and CYP19A1) by forming hydrogen bonds and hydrophobic interactions with these proteins. This study presents the first evidence that malathion triggers spermatogenesis dysfunction in mice through activating the HIF-1/MAPK/PI3K pathway, providing a comprehensive understanding of the reproductive toxicity risks associated with organophosphorus pesticides.
Insights
Malathion pesticide exposure harms male reproductive health by disrupting hormone balance and causing testicular damage. It activates the hypoxia-inducible factor 1 (HIF-1) pathway, leading to impaired sperm production.
Area of Science:
- Environmental Toxicology
- Reproductive Biology
- Molecular Endocrinology
Background:
- Chemical-induced reproductive dysfunction is a significant global health issue.
- Organophosphorus pesticides, like malathion, are widely used and pose potential risks.
Purpose of the Study:
- To investigate the reproductive toxicity of malathion in adolescent male mice.
- To elucidate the molecular mechanisms underlying malathion's adverse effects on testicular function.
Main Methods:
- Exposure of adolescent male mice to environmentally relevant concentrations of malathion for eight weeks.
- Assessment of reproductive parameters, hormone levels, testicular histology, and oxidative stress.
- Testicular RNA sequencing to analyze gene expression changes in key pathways.
- Molecular docking to predict interactions between malathion and target proteins.
Main Results:
- Malathion exposure reduced testis weight, altered sex and thyroid hormones, and caused testicular damage and oxidative stress.
- RNA sequencing revealed malathion's impact on energy metabolism, hypoxia-inducible factor 1 (HIF-1) signaling, and steroid hormone biosynthesis.
- Malathion upregulated HIF-1α expression via the MAPK and PI3K pathways, promoting hypoxia and inhibiting normoxia.
- Molecular docking confirmed malathion's interaction with HIF-1α and steroid hormone synthases.
Conclusions:
- Malathion exposure induces spermatogenesis dysfunction in male mice by activating the HIF-1/MAPK/PI3K pathway.
- This study provides novel insights into the reproductive toxicity mechanisms of organophosphorus pesticides.
- Findings highlight the need for careful risk assessment of pesticide exposure on reproductive health.
