Transgenerational inheritance of diabetes susceptibility in male offspring with maternal androgen exposure.

Summary

Maternal hyperandrogenism imprints heritable DNA methylation patterns in sperm that suppress β-cell function genes, causing transgenerational hyperglycaemia and glucose intolerance in male offspring. Caloric restriction and metformin reversed hyperglycaemia and prevented transmission by normalizing sperm methylation in mice, with human cohort data corroborating sperm/blood methylation signatures.

Key Findings

• Maternal hyperandrogenism predisposed sons to β-cell dysfunction in a large mother–child cohort.
• Prenatal androgen exposure in mice caused hyperglycaemia and glucose intolerance across three generations, worsened by aging and high-fat diet.
• AE-F1 sperm showed differential DNA methylation of β-cell functional genes; methylation marks transmitted to AE-F2 islets and sperm, reducing expression of Pdx1, Irs1, Ptprn2, Cacna1c.
• Caloric restriction and metformin normalized hyperglycaemia and blocked heritable transmission by restoring aberrant sperm DNA methylation.
• Human data corroborated methylation signatures in AE-F1 sperm and in blood of sons of hyperandrogenic mothers.

Clinical Implications

Highlights the importance of managing hyperandrogenism (e.g., in PCOS) before and during pregnancy and suggests development of sperm/blood methylation biomarkers for risk stratification; points to metformin/lifestyle interventions as potential strategies to mitigate intergenerational metabolic risk.

Limitations

• Exact human cohort sample size and demographics not specified in the abstract
• Causality in humans cannot be definitively established without interventional or longitudinal mechanistic trials

Future Directions

Validate methylation biomarkers for risk prediction in sons of hyperandrogenic mothers; test preconception and antenatal interventions (e.g., metformin, lifestyle) in clinical trials to reduce transgenerational diabetes risk.