Maternal androgen exposure induces intergenerational effects via paternal inheritance

Area of Science:

• Reproductive biology
• Endocrinology
• Epigenetics

Background:

• Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with unclear etiology.
• Prenatal androgen exposure is a suspected contributing factor to PCOS development.
• Intergenerational effects of environmental exposures are increasingly recognized.

Purpose of the Study:

• To investigate the intergenerational inheritance of PCOS-like phenotypes in mice following maternal testosterone exposure.
• To explore the underlying molecular mechanisms, including epigenetic modifications, involved in this inheritance.

Main Methods:

• Maternal testosterone exposure in F0 mice.
• Assessment of serum hormone levels and reproductive system development in F1 male and F2 female offspring.
• Analysis of N6-methyladenosine (m6A) modification, mRNA methylation, and protein expression in relevant tissues.
• Investigation of the mTOR and FoxO3 signaling pathways.

Main Results:

• Prenatal testosterone exposure led to impaired serum hormone levels and reproductive development in F1 males and F2 females.
• Downregulated m6A machinery in F1 male testes resulted in mRNA hypomethylation, including Fzd6.
• Decreased FZD6 protein in F2 female ovaries inhibited mTOR signaling and activated FoxO3 phosphorylation, impairing follicular development.

Conclusions:

• Maternal testosterone exposure can induce PCOS-like phenotypes in subsequent generations through male offspring.
• Epigenetic modifications, specifically altered m6A methylation impacting the mTOR signaling pathway via FZD6, are implicated in this intergenerational transmission.
• These findings highlight the role of epigenetic mechanisms in transmitting environmentally induced reproductive disorders across generations.