title: Tertiary Epimutations - A Novel Aspect of Epigenetic Transgenerational Inheritance Promoting Genome Instability.
abstract: 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.
authors.affiliation: Department of Biology, University of Texas at San Antonio, San Antonio, TX United States of America.
authors.forename: John R
authors.initials: JR
authors.lastname: McCarrey
authors.affiliation: Department of Biology, University of Texas at San Antonio, San Antonio, TX United States of America.
authors.forename: Jake D
authors.initials: JD
authors.lastname: Lehle
authors.affiliation: Department of Biology, University of Texas at San Antonio, San Antonio, TX United States of America.
authors.forename: Seetha S
authors.initials: SS
authors.lastname: Raju
authors.affiliation: Department of Biology, University of Texas at San Antonio, San Antonio, TX United States of America.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA United States of America.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Nilsson
authors.affiliation: Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA United States of America.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Skinner
mesh_terms: D000818:Animals; D052244:Endocrine Disruptors / Q000494:pharmacology*; D044127:Epigenesis, Genetic; D005260:Female; D017930:Genes, Reporter; D042822:Genomic Instability; D040582:Inheritance Patterns; D007668:Kidney / Q000187:drug effects*; D008297:Male; D009154:Mutation; D059645:Mutation Rate; D010080:Oxazoles / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D013094:Spermatozoa / Q000187:drug effects*
chemical_list: D052244:Endocrine Disruptors; D010080:Oxazoles; C025643:vinclozolin