Intronic miR-140-5p contributes to beta-cypermethrin-mediated testosterone decline

Area of Science:

• Endocrinology
• Toxicology
• Molecular Biology

Background:

• Beta-cypermethrin (β-CYP) is a pyrethroid pesticide with known anti-androgenic effects.
• Pesticide exposure can lead to male reproductive dysfunction, but the underlying molecular mechanisms are not fully understood.

Purpose of the Study:

• To investigate the roles of MAPK pathways, DNA methyltransferases (DNMTs), and microRNAs (miRNAs) in β-CYP-induced testicular dysfunction.
• To elucidate the molecular cascade responsible for β-CYP's anti-androgenic effects and impact on male reproduction.

Main Methods:

• Utilized Sprague-Dawley rats and isolated Leydig cells for experimental exposure to β-CYP.
• Assessed plasma testosterone levels, testicular histomorphology, and Leydig cell function.
• Investigated MAPK pathway activation (JNK, p38), gene/protein expression (c-Jun, Sp1, DNMT3α, StAR, P450scc, 3β-HSD, 5α-reductase).
• Employed techniques including Co-IP, ChIP, qPCR, and gene silencing/overexpression to determine molecular interactions.

Main Results:

• β-CYP exposure decreased testosterone levels and caused testicular damage, including altered Leydig cell function.
• JNK and p38/MAPK pathways were inactivated, leading to reduced DNMT3α activity and expression.
• β-CYP induced miR-140-5p, which suppressed steroidogenic genes (StAR, P450scc, 3β-HSD) by targeting SF-1.
• SF-1 positively regulated steroidogenic gene expression.
• 5α-reductase expression was downregulated post-β-CYP exposure.

Conclusions:

• β-CYP exhibits anti-androgenic properties, critically impairing male reproduction.
• A molecular cascade involving DNMT3α, miR-140-5p, and SF-1, co-regulated by JNK/p38 pathways, mediates β-CYP-induced testosterone decline.
• Downregulation of 5α-reductases may represent a compensatory mechanism against β-CYP toxicity.