Exposure to low-dose bisphenol A impairs meiosis in the rat seminiferous tubule culture model: a physiotoxicogenomic approach

PLoS One. 2014 Sep 2;9(9):e106245. doi: 10.1371/journal.pone.0106245. eCollection 2014.

Abstract

Background: Bisphenol A (BPA) is one of the most widespread chemicals in the world and is suspected of being responsible for male reproductive impairments. Nevertheless, its molecular mode of action on spermatogenesis is unclear. This work combines physiology and toxicogenomics to identify mechanisms by which BPA affects the timing of meiosis and induces germ-cell abnormalities.

Methods: We used a rat seminiferous tubule culture model mimicking the in vivo adult rat situation. BPA (1 nM and 10 nM) was added to the culture medium. Transcriptomic and meiotic studies were performed on the same cultures at the same exposure times (days 8, 14, and 21). Transcriptomics was performed using pangenomic rat microarrays. Immunocytochemistry was conducted with an anti-SCP3 antibody.

Results: The gene expression analysis showed that the total number of differentially expressed transcripts was time but not dose dependent. We focused on 120 genes directly involved in the first meiotic prophase, sustaining immunocytochemistry. Sixty-two genes were directly involved in pairing and recombination, some of them with high fold changes. Immunocytochemistry indicated alteration of meiotic progression in the presence of BPA, with increased leptotene and decreased diplotene spermatocyte percentages and partial meiotic arrest at the pachytene checkpoint. Morphological abnormalities were observed at all stages of the meiotic prophase. The prevalent abnormalities were total asynapsis and apoptosis. Transcriptomic analysis sustained immunocytological observations.

Conclusion: We showed that low doses of BPA alter numerous genes expression, especially those involved in the reproductive system, and severely impair crucial events of the meiotic prophase leading to partial arrest of meiosis in rat seminiferous tubule cultures.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzhydryl Compounds / pharmacology*
  • Cell Nucleus / drug effects
  • Cells, Cultured
  • Down-Regulation / drug effects
  • Gene Expression Profiling
  • Male
  • Meiosis / drug effects*
  • Models, Biological*
  • Oligonucleotide Array Sequence Analysis
  • Phenols / pharmacology*
  • Rats, Sprague-Dawley
  • Recombination, Genetic / genetics
  • Reproducibility of Results
  • Seminiferous Tubules / cytology*
  • Seminiferous Tubules / drug effects
  • Seminiferous Tubules / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Spermatocytes / cytology
  • Spermatocytes / drug effects
  • Synaptonemal Complex / drug effects
  • Synaptonemal Complex / genetics
  • Toxicogenetics*
  • Transcriptome / genetics
  • Up-Regulation / drug effects

Substances

  • Benzhydryl Compounds
  • Phenols
  • bisphenol A

Grant support

The Research Consortium ECCOREV n° 3098 (Ecosystemes Continentaux et Risques Environnementaux) CNRS/Aix-Marseille Université funded this study (AOI 2010, grant number 7). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.