Caloric restriction prevents inheritance of polycystic ovary syndrome through oocyte-mediated DNA methylation reprogramming.

Summary

Using IVF-ET and surrogacy to isolate the oocyte’s role, the authors show that oocytes from androgen-exposed mice transmit PCOS-like traits to F2 and F3 offspring. Caloric restriction in F1 or F2 prevents this transmission by restoring oocyte DNA methylation in insulin secretion and AMPK signaling genes; dysregulated methylation/expression (e.g., Adcy3, Gnas, Srebf1) in offspring tissues is reversed, with supportive signals from human embryonic methylomes in women with PCOS.

Key Findings

• Oocytes from androgen-exposed F1 mice transmitted PCOS-like traits to F2 and F3 via IVF-ET and surrogacy.
• Caloric restriction in F1 or F2 prevented transmission by restoring oocyte DNA methylation in insulin secretion and AMPK signaling genes.
• Aberrant DNA methylation and expression of genes such as Adcy3, Gnas, and Srebf1 in offspring tissues were reversed by maternal caloric restriction.
• Comparable benefits of caloric restriction were observed in aberrant embryonic methylomes from women with PCOS.

Clinical Implications

Although preclinical, findings support counseling women with PCOS on preconception metabolic optimization. They motivate trials testing structured caloric restriction or metabolic interventions before conception to reduce intergenerational risk.

Limitations

• Preclinical mouse model limits direct clinical generalizability
• Exact sample sizes and effect sizes per comparison are not specified
• Feasibility and adherence to caloric restriction in humans require evaluation

Future Directions

Prospective human preconception trials testing structured caloric restriction or metabolic optimization on oocyte epigenome and offspring outcomes; mapping cell-type-specific methylome changes and defining minimal effective dosing/timing.