Transgenerational Epigenetics

For this review of epigenetic transgenerational inheritance, it will be useful to provide some historical context. To that end, the initial experiments from the authors’ laboratory describing the phenomenon of epigenetic transgenerational inheritance will be outlined, and issues related to investigations in this field will be discussed using these studies as an example.1 Historically, the authors were investigating the actions of two environmental toxicants (the fungicide vinclozolin and the pesticide methoxychlor) following an exposure of an F0 generation gestating rat during fetal gonadal sex determination, and characterizing the effects of the toxicants on gonadal development and function.2,3 A serendipitous observation was made when a postdoctoral fellow in the laboratory mistakenly bred the F1 generation to generate an F2 generation. Upon analysis of the F2 generation testis phenotype, over 90% of the males had a spermatogenic cell apoptosis defect. This prompted a multiple year study to further investigate this surprising observation and culminated in one of the first observations of the environmentally induced epigenetic transgenerational inheritance of disease.1 This study demonstrated the transmission of testis spermatogenic cell apoptosis to the F1, F2, F3, and F4 generations, as well as to an outcrossed generation in which affected male rats were bred to wild-type females. This phenotype was transmitted through non-Mendelian genetic inheritance and affected 90% of the male population. The epigenetic effects on the sperm were identified as changes in DNA methylation at specific sites.1 The impact of this study on our understanding of the molecular control of inheritance, disease etiology, and environmental toxicology is significant. Over the past 10 years, a series of studies have further investigated this phenomenon in a number of different laboratories. Although an exhaustive review of the literature is not provided here, the major issues are discussed. There are specific issues that need to be addressed in order to better understand epigenetic transgenerational inheritance. These include environmental factor specificity, i.e., whether different environmental toxicants would produce similar phenomena. Another issue is germline epigenetics and the mode of transmission of disease transgenerationally. A final issue involves disease etiology, or how it is that an epigenetic change during fetal development can result in a disease phenotype in adult animals several generations later.4,5