Differential DNA Methylation Regions in Adult Human Sperm following Adolescent Chemotherapy: Potential for Epigenetic Inheritance

Margarett Shnorhavorian; Stephen M Schwartz; Barbara Stansfeld; Ingrid Sadler-Riggleman; Daniel Beck; Michael K Skinner

doi:10.1371/journal.pone.0170085

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Differential DNA Methylation Regions in Adult Human Sperm following Adolescent Chemotherapy: Potential for Epigenetic Inheritance

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Differential DNA Methylation Regions in Adult Human Sperm following Adolescent Chemotherapy: Potential for Epigenetic Inheritance

Margarett Shnorhavorian, Stephen M Schwartz, Barbara Stansfeld, Ingrid Sadler-Riggleman, Daniel Beck and Michael K Skinner

PloS one, Vol.12(2), pp.e0170085-e0170085

2017

DOI: https://doi.org/10.1371/journal.pone.0170085

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https://hdl.handle.net/2376/110647

PMCID: PMC5287489

PMID: 28146567

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Abstract

Age Factors

Epigenesis, Genetic

Antineoplastic Agents - therapeutic use

Chromosome Mapping

Spermatozoa - metabolism

Spermatozoa - drug effects

DNA Copy Number Variations

Neoplasms - drug therapy

Young Adult

DNA Methylation

Chromatin Immunoprecipitation

Neoplasms - genetics

Antineoplastic Agents - adverse effects

Adolescent

CpG Islands

High-Throughput Nucleotide Sequencing

Mutation

The potential that adolescent chemotherapy can impact the epigenetic programming of the germ line to influence later life adult fertility and promote epigenetic inheritance was investigated. Previous studies have demonstrated a number of environmental exposures such as abnormal nutrition and toxicants can promote sperm epigenetic changes that impact offspring. Adult males approximately ten years after pubertal exposure to chemotherapy were compared to adult males with no previous exposure. Sperm were collected to examine differential DNA methylation regions (DMRs) between the exposed and control populations. Gene associations and correlations to genetic mutations (copy number variation) were also investigated. A signature of statistically significant DMRs was identified in the chemotherapy exposed male sperm. The DMRs, termed epimutations, were found in CpG desert regions of primarily 1 kilobase size. Observations indicate adolescent chemotherapy exposure can promote epigenetic alterations that persist in later life. This is the first observation in humans that an early life chemical exposure can permanently reprogram the spermatogenic stem cell epigenome. The germline (i.e., sperm) epimutations identified suggest chemotherapy has the potential to promote epigenetic inheritance to the next generation.

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Title: Differential DNA Methylation Regions in Adult Human Sperm following Adolescent Chemotherapy: Potential for Epigenetic Inheritance
Creators: Margarett Shnorhavorian - Seattle Children's Research Institute, Seattle, Washington, United States of America
Stephen M Schwartz - Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
Barbara Stansfeld - Seattle Children's Research Institute, Seattle, Washington, United States of America
Ingrid Sadler-Riggleman - Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, Washington, United States of America
Daniel Beck - Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, Washington, United States of America
Michael K Skinner - Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, Washington, United States of America
Publication Details: PloS one, Vol.12(2), pp.e0170085-e0170085
Academic Unit: Biological Sciences, School of
Publisher: United States
Grant note: R01 ES012974 / NIEHS NIH HHS
Identifiers: 99900547133501842
Language: English
Resource Type: Journal article