Environmentally Induced Epigenetic Transgenerational Inheritance of Ovarian Disease

Abstract

The actions of environmental toxicants and relevant mixtures in promoting the epigenetic transgenerational inheritance of ovarian disease was investigated with the use of a fungicide, a pesticide mixture, a plastic mixture, dioxin and a hydrocarbon mixture. After transient exposure of an F0 gestating female rat during embryonic gonadal sex determination, the F1 and F3 generation progeny adult onset ovarian disease was assessed. Transgenerational disease phenotypes observed included an increase in cysts resembling human polycystic ovarian disease (PCO) and a decrease in the ovarian primordial follicle pool size resembling primary ovarian insufficiency (POI). The F3 generation granulosa cells were isolated and found to have a transgenerational effect on the transcriptome and epigenome (differential DNA methylation). Epigenetic biomarkers for environmental exposure and associated gene networks were identified. Epigenetic transgenerational inheritance of ovarian disease states was induced by all the different classes of environmental compounds, suggesting a role of environmental epigenetics in ovarian disease etiology.

Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency

“…These results are in agreement with previous studies which also found transgenerational increases in susceptibility to ovarian diseases after exposure of F0 generation pregnant rats to vinclozolin [15] or DDT [16]. Experimental exposure of pregnant rats to other environmental toxicants such as jet fuel hydrocarbons, the plastics compounds bisphenol A (BPA) and phthalates, the pesticides permethrin and methoxychlor, and the industrial pollutant dioxin have also been shown to promote a transgenerational increase in ovarian disease [15,42]. This suggests that the ovary may be particularly sensitive to transgenerational epigenetic perturbations that disrupt somatic cell gene expression.…”

“…This finding is consistent with previous work in which transgenerational DMR in sperm were most often found in regions of low CpG density after ancestral toxicant exposure [25–29]. A previous study has also examined changes in DNA methylation in granulosa cells after ancestral exposure to vinclozolin [15]. This investigation used granulosa cells from 5–6-month-old F3 generation rats from vinclozolin and control lineages analyzed using a methylated DNA immunoprecipitation procedure (MeDIP) followed by a gene promoter microarray chip analysis.…”

“…This suggests that the ovary may be particularly sensitive to transgenerational epigenetic perturbations that disrupt somatic cell gene expression. Interestingly, these earlier studies demonstrated that the F1 generation direct fetal exposure did not induce ovarian disease later in life (1 y of age), but did promote ovarian disease in the transgenerational F3 generation at 1 y of age [15,42]. The exception was BPA and phthalate exposure that did promote ovarian diseases in both the F1 and F3 generations.…”

“…Exposure of gestating female rats (F0 generation) to the agricultural fungicide vinclozolin resulted in a transgenerational increase in ovarian abnormalities in great-grand-offspring (F3 generation) [15]. These abnormalities included a decrease in the primordial follicle pool of oocytes that was similar to what is seen in POI, and an increase in ovarian cysts that was similar to what is seen in PCOS.…”

“…These abnormalities included a decrease in the primordial follicle pool of oocytes that was similar to what is seen in POI, and an increase in ovarian cysts that was similar to what is seen in PCOS. In addition, the ovarian granulosa cells from the antral follicles of 6-month-old F3 generation vinclozolin lineage rats showed transgenerational changes in gene expression and alterations in the pattern of DNA methylation compared to F3 generation control lineage rats [15]. Similarly, exposure of F0 generation pregnant rats to the insecticide DDT (dichlorodiphenyltrichloroethane) induced an epigenetic transgenerational increase in ovarian diseases in the F3 generation, which was comprized of primordial follicle loss and increased rates of ovarian cysts [16].…”