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Paternal Sperm Gnas-ICR Epigenetic Programming Contributes to PPP-Like Phenotypes in Female Offspring

Jing Huang1,2,3, Lu Chen4, Tiancheng Wu1

  • 1Department of Gynaecology and Obstetrics, Zhongnan Hospital of Wuhan University, Wuhan, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 28, 2026
PubMed

Insights

Paternal caffeine exposure before conception can cause precocious puberty (PPP) in female offspring, persisting for generations. This is linked to epigenetic changes in sperm affecting offspring ovarian development.

Area of Science:

  • Endocrinology
  • Reproductive Biology
  • Epigenetics

Background:

  • Peripheral precocious puberty (PPP) incidence is rising, particularly in females.
  • Paternal factors influencing PPP development are not well understood.

Purpose of the Study:

  • To investigate the impact of paternal preconception caffeine exposure (PPCE) on female offspring's reproductive development.
  • To elucidate the underlying epigenetic mechanisms involving sperm and offspring ovaries.

Main Methods:

  • Utilized a rat model exposing fathers to caffeine preconception.
  • Analyzed sperm and offspring ovarian tissues for epigenetic modifications (DNA methylation) and gene expression.
  • Conducted gain- and loss-of-function studies of Gnas and glucocorticoid receptor (GR) antagonism.

Main Results:

  • PPCE induced PPP-like phenotypes in female offspring, with transgenerational effects into the F2 generation.
  • PPCE altered paternal glucocorticoid levels and sperm Gnas imprinting control region (ICR) hypermethylation.
  • Offspring ovaries showed increased Gnas-ICR methylation, altered Gnas/Nespas expression, activated cAMP/PKA/CREB pathway, and enhanced estrogen synthesis.
  • Paternal GR antagonism mitigated these epigenetic and phenotypic changes.

Conclusions:

  • Paternal preconception endocrine status, specifically glucocorticoid levels, can epigenetically program offspring ovarian development via sperm Gnas-ICR methylation.
  • This provides a preclinical model for understanding paternal influences on reproductive health and PPP.
  • Findings suggest a link between paternal endocrine status, sperm epigenetics, and offspring reproductive outcomes.

Keywords:
Gnas‐ICRestrogen synthesisimprinted genespaternal exposureperipheral precocious pubertysperm reprogramming

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