Ex vivo exposures to arsenite and its methylated trivalent metabolites alter gene transcription in mouse sperm cells

Toxicol Appl Pharmacol. 2022 Nov 15:455:116266. doi: 10.1016/j.taap.2022.116266. Epub 2022 Oct 7.


We have previously reported that preconception exposure to iAs may contribute to the development of diabetes in mouse offspring by altering gene expressions in paternal sperm. However, the individual contributions of iAs and its methylated metabolites, monomethylated arsenic (MAs) and dimethylated arsenic (DMAs), to changes in the sperm transcriptome could not be determined because all three As species are present in sperm after in vivo iAs exposure. The goal of the present study was to assess As species-specific effects using an ex vivo model. We exposed freshly isolated mouse sperm to either 0.1 or 1 μM arsenite (iAsIII) or the methylated trivalent arsenicals, MAsIII and DMAsIII, and used RNA-sequencing to identify differentially expressed genes, enriched pathways, and associated protein networks. For all arsenicals tested, the exposures to 0.1 μM concentrations had greater effects on gene expression than 1 μM exposures. Transcription factor AP-1 and B cell receptor complexes were the most significantly enriched pathways in sperm exposed to 0.1 μM iAsIII. The Mre11 complex and Antigen processing were top pathways targeted by exposure to 0.1 μM MAsIII and DMAsIII, respectively. While there was no overlap between gene transcripts altered by ex vivo exposures in the present study and those altered by in vivo exposure in our prior work, several pathways were shared, including PI3K-Akt signaling, Focal adhesion, and Extracellular matrix receptor interaction pathways. Notably, the protein networks associated with these pathways included those with known roles in diabetes. This study is the first to assess the As species-specific effects on sperm transcriptome, linking these effects to the diabetogenic effects of iAs exposure.

Keywords: Arsenic; Diabetes; Methylated trivalent arsenicals; Sperm; Transcriptomic effects.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arsenic* / metabolism
  • Arsenicals* / pharmacology
  • Arsenites* / metabolism
  • Arsenites* / toxicity
  • Diabetes Mellitus* / metabolism
  • Male
  • Methylation
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA / metabolism
  • Receptors, Antigen, B-Cell / metabolism
  • Semen / metabolism
  • Spermatozoa / metabolism
  • Transcription Factor AP-1 / metabolism
  • Transcription, Genetic


  • arsenite
  • Arsenites
  • Arsenic
  • Proto-Oncogene Proteins c-akt
  • Phosphatidylinositol 3-Kinases
  • Transcription Factor AP-1
  • Arsenicals
  • RNA
  • Receptors, Antigen, B-Cell