Tertiary Epimutations - A Novel Aspect of Epigenetic Transgenerational Inheritance Promoting Genome Instability

• Published in: PloS one Vol. 11; no. 12; p. e0168038
• Main Authors: McCarrey, John R, Lehle, Jake D, Raju, Seetha S, Wang, Yufeng, Nilsson, Eric E, Skinner, Michael K
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.12.2016; Public Library of Science (PLoS)
• Subjects: Accumulation; Analysis; Animals; Biology and Life Sciences; Disease transmission; DNA methylation; Endocrine Disruptors - pharmacology; Environmental factors; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Exposure; Female; Gene mutation; Genes, Reporter; Genomes; Genomic Instability; Heredity; Inheritance Patterns; Intrauterine exposure; Kidney - drug effects; Kidneys; Male; Medicine and Health Sciences; Mutation; Mutation Rate; Oxazoles - pharmacology; Pregnancy; Progeny; Rats; Spermatozoa - drug effects; Stability; Stem cells; Vinclozolin; United States
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0168038

Exposure to environmental factors can induce the epigenetic transgenerational inheritance of disease. Alterations to the epigenome termed "epimutations" include "primary epimutations" which are epigenetic alterations in the absence of genetic change and "secondary epimutations" which form following an initial genetic change. To determine if secondary epimutations contribute to transgenerational transmission of disease following in utero exposure to the endocrine disruptor vinclozolin, we exposed pregnant female rats carrying the lacI mutation-reporter transgene to vinclozolin and assessed the frequency of mutations in kidney tissue and sperm recovered from F1 and F3 generation progeny. Our results confirm that vinclozolin induces primary epimutations rather than secondary epimutations, but also suggest that some primary epimutations can predispose a subsequent accelerated accumulation of genetic mutations in F3 generation descendants that have the potential to contribute to transgenerational phenotypes. We therefore propose the existence of "tertiary epimutations" which are initial primary epimutations that promote genome instability leading to an accelerated accumulation of genetic mutations.