Nicotine inhibits murine Leydig cell differentiation and maturation via regulating Hedgehog signal pathway

Area of Science:

• Reproductive Biology
• Toxicology
• Molecular Endocrinology

Background:

• Nicotine is a primary toxicant in cigarette smoke with known adverse effects on male reproductive health.
• Leydig cells are crucial for testosterone production, directly impacting male fertility.
• Previous studies suggest nicotine affects Leydig cell function, but the underlying molecular mechanisms remain unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms by which nicotine impairs Leydig cell differentiation and maturation in mice.
• To investigate the role of the Hedgehog signaling pathway in nicotine-induced reproductive toxicity.

Main Methods:

• C57BL/6J mice were divided into control and nicotine-treated groups.
• Next-generation RNA sequencing and bioinformatics analysis were performed on isolated Leydig cells.
• Key protein and gene expression levels related to the Hedgehog pathway were quantified.

Main Results:

• Nicotine significantly altered the expression of 7 key signaling pathways in Leydig cells.
• The Hedgehog signaling pathway, critical for Leydig cell differentiation, was notably affected.
• Nicotine promoted Gli2 destabilization and degradation via GSK3β-mediated phosphorylation and β-TrCP-induced ubiquitination, downregulating target genes like PTCH1.

Conclusions:

• Nicotine inhibits Leydig cell differentiation and maturation by disrupting the Hedgehog signaling pathway.
• This disruption leads to reduced androgen secretion and negatively impacts male reproductive function.
• Targeting the Hedgehog pathway may offer therapeutic strategies against nicotine-induced male infertility.