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.
Highlights
Since the initial report of the induction of epigenetic transgenerational inheritance of adult-onset disease in F3 generation progeny from an F0 generation gestating female rat exposed to the endocrine disruptor vinclozolin [1], there have been numerous reports of similar effects caused by exposure of fetuses or adults to a variety of different environmental factors, as well as reports of epigenetic transgenerational inheritance in numerous additional species [1,4,5,6,7,8,9]
No significant differences in frequencies of mutations were observed between vinclozolin- and control-lineage kidney or sperm samples, respectively, except for one vinclozolin-lineage sperm sample in which we detected a mutation frequency that was significantly lower than the mean frequency of the F1 generation control-lineage sperm samples (p = 0.0352)
Previous studies in the mouse revealed enhanced maintenance of genetic integrity in germline cells relative to that in differentiated somatic cells [31,36]. This distinction was not as robust between rat germ cells and somatic cells. These data confirm previous reports that vinclozolin is not directly mutagenic [37], and suggest that neither the immediate phenotypic abnormalities observed in vinclozolin-lineage F1 generation offspring nor the transmission of those defects to the F2 generation can be ascribed to the direct induction of genetic mutations
Summary
Since the initial report of the induction of epigenetic transgenerational inheritance of adult-onset disease in F3 generation progeny from an F0 generation gestating female rat exposed to the endocrine disruptor vinclozolin [1], there have been numerous reports of similar effects caused by exposure of fetuses or adults to a variety of different environmental factors (see [2,3] for reviews), as well as reports of epigenetic transgenerational inheritance in numerous additional species [1,4,5,6,7,8,9]. Tertiary Epimutations systems and fertility in both sexes, the incidence of cancer, the immune system, kidney function, the prostate, obesity, cardiovascular function, growth, insulin sensitivity, glucose tolerance, pulmonary function, neuronal function and social behavior, among other effects [3] These reports have revealed a novel etiology of adult-onset disease and a mechanism underlying the developmental origins of health and disease (DOHAD) [10]. These observations suggest that the phenomenon of epigenetic transgenerational inheritance of disease is significantly more extensive than previously thought
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