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Estradiol represses insulin-like 3 expression and promoter activity in MA-10 Leydig cells

Eric Laguë1, Jacques J Tremblay

  • 1Reproduction, Perinatal and Child Health, CHUQ Research Centre, Quebec, Canada, G1V 4G2.

Toxicology
|May 12, 2009
PubMed

Insights

Estradiol exposure harms male reproductive development by suppressing INSL3 gene expression in Leydig cells. Testosterone can counteract these detrimental effects, offering potential therapeutic insights.

Area of Science:

  • Reproductive Biology
  • Endocrinology
  • Molecular Toxicology

Background:

  • Endocrine disruptors negatively impact male reproductive system development and function.
  • Estrogen exposure is linked to cryptorchidism, potentially via repression of insulin-like 3 (INSL3).
  • The precise molecular mechanism of estrogen's effect on INSL3 expression is not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanism by which estradiol (E(2)) represses INSL3 gene expression in Leydig cells.
  • To identify the regulatory regions and factors involved in E(2)-mediated repression of the INSL3 promoter.

Main Methods:

  • Utilized MA-10 Leydig cells as a model system.
  • Measured INSL3 mRNA levels following estradiol treatment.
  • Analyzed human and mouse INSL3 promoter activity using reporter assays.
  • Performed site-directed mutagenesis on the INSL3 promoter to investigate the role of specific nuclear receptor binding sites.

Main Results:

  • Estradiol (E(2)) significantly repressed INSL3 mRNA levels and promoter activity in MA-10 cells.
  • The E(2)-responsive region was localized to the proximal human INSL3 promoter, lacking a consensus estrogen response element.
  • Mutation of NUR77 and SF1 binding sites abolished E(2)-induced repression.
  • Testosterone treatment counteracted the repressive effect of E(2) on INSL3 transcription.

Conclusions:

  • Estradiol represses INSL3 transcription in Leydig cells through an indirect mechanism involving NUR77 and SF1.
  • These findings provide crucial insights into how estrogen disrupts male reproductive development.
  • Testosterone acts as a key regulator, potentially mitigating estrogen's adverse effects on INSL3 expression.

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