Dioxin (TCDD) Induces Epigenetic Transgenerational Inheritance of Adult Onset Disease and Sperm Epimutations

Abstract

Environmental compounds can promote epigenetic transgenerational inheritance of adult-onset disease in subsequent generations following ancestral exposure during fetal gonadal sex determination. The current study examined the ability of dioxin (2,3,7,8-tetrachlorodibenzo[p]dioxin, TCDD) to promote epigenetic transgenerational inheritance of disease and DNA methylation epimutations in sperm. Gestating F0 generation females were exposed to dioxin during fetal day 8 to 14 and adult-onset disease was evaluated in F1 and F3 generation rats. The incidences of total disease and multiple disease increased in F1 and F3 generations. Prostate disease, ovarian primordial follicle loss and polycystic ovary disease were increased in F1 generation dioxin lineage. Kidney disease in males, pubertal abnormalities in females, ovarian primordial follicle loss and polycystic ovary disease were increased in F3 generation dioxin lineage animals. Analysis of the F3 generation sperm epigenome identified 50 differentially DNA methylated regions (DMR) in gene promoters. These DMR provide potential epigenetic biomarkers for transgenerational disease and ancestral environmental exposures. Observations demonstrate dioxin exposure of a gestating female promotes epigenetic transgenerational inheritance of adult onset disease and sperm epimutations.

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

“…The sites of these DMRs were in genomic regions of relatively low CpG density ‘CpG deserts’ [32]. 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].…”

“…There was no increase in ovarian disease in direct fetal exposed F1 or germline exposed F2 generation vinclozolin or DDT lineage rats compared to controls [30,31]. Therefore, as previously observed with most exposures, negligible ovarian disease is present following direct exposure [25,27–29], with the exception of BPA and phthalates [26]. This indicates that there was an epigenetic transgenerational increase in susceptibility to ovarian disease in rats ancestrally exposed to DDT or vinclozolin (Figure 1).…”

“…Pregnant F0 generation female rats were transiently exposed to vinclozolin, DDT or control vehicle (dimethyl sulfoxide, DMSO) from days 8–14 of gestation, as described in Methods [25]. The in utero exposed offspring (F1 generation rats) were bred to produce the F2 generation, and similarly the F2 generation animals were bred to produce the transgenerational F3 generation.…”

“…There was a significant increase in ovarian disease in transgenerational F3 generation DDT and vinclozolin lineage rats at one year of age compared to F3 generation controls (Figure 1). Previous studies have shown that transgenerational increases in ovarian disease were detected following exposures to plastic derived compounds bisphenol A (BPA) and phthalates (DBT & DEHP) [26], dioxin (TCCD) [25], pesticides permethrin and DEET [27], jet fuel hydrocarbons [28], and methoxychlor [29], with nearly 100% disease frequency. Therefore, the transgenerational inheritance of increased ovarian disease can occur after exposure to a variety of environmental toxicants.…”

Ancestral TCDD exposure promotes epigenetic transgenerational inheritance of imprinted gene Igf2: Methylation status and DNMTs

“…So far, the effect on imprinted gene upon ancestral TCDD exposure has been mainly focusing on the fetus (Wu et al, 2004), the reproductive organs or the germ cells (Manikkam et al, 2012). Although, one study has explored the effects of maternal exposure to TCDD on imprinted genes Snrpn, Peg3 and Igf2r in the liver of the F1 male mouse (Somm et al, 2013), whether epigenetic transgenerational effects existing in the somatic tissue are not yet known.…”