Chronic exposure to cadmium induces differential methylation in mice spermatozoa

Wesley N. Saintilnord, Sara Y.N. Tenlep, Joshua D. Preston, Eleonora Duregon, Jason E. DeRouchey, Jason M. Unrine, Rafael de Cabo, Kevin J. Pearson, Yvonne N. Fondufe-Mittendorf

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Cadmium exposure is ubiquitous and has been linked to diseases including cancers and reproductive defects. Since cadmium is nonmutagenic, it is thought to exert its gene dysregulatory effects through epigenetic reprogramming. Several studies have implicated germline exposure to cadmium in developmental reprogramming. However, most of these studies have focused on maternal exposure, while the impact on sperm fertility and disease susceptibility has received less attention. In this study, we used reduced representation bisulfite sequencing to comprehensively investigate the impact of chronic cadmium exposure on mouse spermatozoa DNA methylation. Adult male C57BL/J6 mice were provided water with or without cadmium chloride for 9 weeks. Sperm, testes, liver, and kidney tissues were collected at the end of the treatment period. Cadmium exposure was confirmed through gene expression analysis of metallothionein-1 and 2, 2 well-known cadmium-induced genes. Analysis of sperm DNA methylation changes revealed 1788 differentially methylated sites present at regulatory regions in sperm of mice exposed to cadmium compared with vehicle (control) mice. Furthermore, most of these differential methylation changes positively correlated with changes in gene expression at both the transcription initiation stage as well as the splicing levels. Interestingly, the genes targeted by cadmium exposure are involved in several critical developmental processes. Our results present a comprehensive analysis of the sperm methylome in response to chronic cadmium exposure. These data, therefore, highlight a foundational framework to study gene expression patterns that may affect fertility in the exposed individual as well as their offspring, through paternal inheritance.

Original languageEnglish
Pages (from-to)262-276
Number of pages15
JournalToxicological Sciences
Issue number2
StatePublished - Apr 1 2021

Bibliographical note

Publisher Copyright:
© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.


  • Cadmium
  • DNA methylation
  • Epigenetics
  • Spermatogenesis

ASJC Scopus subject areas

  • Toxicology


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