Pesticide Methoxychlor Promotes the Epigenetic Transgenerational Inheritance of Adult-Onset Disease through the Female Germline

Abstract

Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures.

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).…”

“…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.…”

Kazanilmiş Epi̇geneti̇k Deği̇şi̇kli̇kleri̇n Kalitimi Ve Hastaliklara Yatkinliktaki̇ Rolü

“…F0 sıçanların hamileliğin 8-14. günleri arasında, pestisit metoksiklora maruz kalması ile yavruların sperm genomunda oluşan epimutasyonların böbrek, yumurtalık hastalıkları ve obezite gibi geç başlangıçlı hastalıkları F3 jenerasyonuna kadar taşıdığı ortaya koyulmuştur (29). ii.…”

Is Male Infertility a Natural Defense or Forerunner of Cancer?

“…Similarly, maternal lifestyle is known to influence son's reproductive function. Particularly, maternal smoking [120] and alcohol consumption during pregnancy can be harmful to the developing testicles [121].…”