Abstract
A number of environmental factors (e.g. toxicants) have been shown to promote the epigenetic transgenerational inheritance of disease and phenotypic variation. Transgenerational inheritance requires the germline transmission of altered epigenetic information between generations in the absence of direct environmental exposures. The primary periods for epigenetic programming of the germ line are those associated with primordial germ cell development and subsequent fetal germline development. The current study examined the actions of an agricultural fungicide vinclozolin on gestating female (F0 generation) progeny in regards to the primordial germ cell (PGC) epigenetic reprogramming of the F3 generation (i.e. great-grandchildren). The F3 generation germline transcriptome and epigenome (DNA methylation) were altered transgenerationally. Interestingly, disruptions in DNA methylation patterns and altered transcriptomes were distinct between germ cells at the onset of gonadal sex determination at embryonic day 13 (E13) and after cord formation in the testis at embryonic day 16 (E16). A larger number of DNA methylation abnormalities (epimutations) and transcriptional alterations were observed in the E13 germ cells than in the E16 germ cells. These observations indicate that altered transgenerational epigenetic reprogramming and function of the male germline is a component of vinclozolin induced epigenetic transgenerational inheritance of disease. Insights into the molecular control of germline transmitted epigenetic inheritance are provided.
Highlights
Induced epigenetic transgenerational inheritance of disease and phenotypic variation involves the germline transmission of altered epigenetic information in the absence of direct exposure [1,2]
Previous research demonstrated that exposure of an F0 generation gestating female to the agricultural fungicide vinclozolin during primordial germ cell (PGC) development in the developing fetuses promotes epigenetic transgenerational inheritance of disease [1,3] and epigenetic alterations in the F3 generation descendants [1,6]
The experimental design involved the exposure of an F0 generation gestating female outbred Spague-Dawley rat during the period of embryonic days 8–14 that correlate with the end of primordial germ cell (PGC) migration and early events of gonadal sex determination [1,2]
Summary
Induced epigenetic transgenerational inheritance of disease and phenotypic variation involves the germline transmission of altered epigenetic information in the absence of direct exposure [1,2]. A number of different environmental toxicants have been shown to promote exposure specific alterations in the F3 generation sperm epigenome (DNA methylation) [7]. The primary site of action of these different environmental factors must be in the germ line in order to promote epigenetic transgenerational inheritance This phenomenon has been demonstrated in a wide variety of species including rats [1,3], humans [19,20], mice [9,21], plants [22,23], worms [24,25], and flies [26,27]. The current study used an outbred rat model [1] and the agricultural fungicide vinclozolin [28] to promote the epigenetic transgenerational inheritance of abnormalities that include testis spermatogenic defects and male infertility [1,29], prostate disease [3,30], kidney disease [3], behavior alterations (e.g. anxiety) [18,31,32], mammary gland tumor development [3], immune abnormalities [3], and ovarian disease [7,33]
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