Epigenetic Transgenerational Actions of Various Environmental Compounds on Pubertal Onset and Gonadal Function

Mohan Manikkam; Rebecca Tracey; Ginger Larsen Beiro; Renee Espinosa Najera; Michael K. Skinner

doi:10.1093/biolreprod/85.s1.278

The transgenerational actions of several environmental contaminants and compound mixtures were investigated including pesticides (permethrin and N,N-Diethyl-meta-toluamide, DEET), plastics (bisphenol-A and phthalates), dioxin (2,3,7,8-Tetrachlorodibenzo-p-dioxin, TCDD) and a hydrocarbon mixture (jet fuel, Jet Propellant 8, JP8). Vinclozolin exposure was used as a positive control and vehicle treatment was used as a negative control with F0 gestating female rat being treated. Treatments were administered during gonadal sex determination from embryonic day 8 through day 14. The effects were considered transgenerational if disease phenotypes were found in the F3 generation offspring. Transgenerational disease phenotypes were observed in F3 generation within and until 120 days of age and they included alterations in the body and gonad weights, in the onset of puberty and in gonadal function. The pubertal onset of females (vaginal opening) and males (balano-preputial separation) was assessed. Gonadal function was examined by ovarian follicular and cyst counts in females and in males by testicular apoptotic germ cell counts (Terminal deoxynucleotidyl transferase dUTP nick end labeling or TUNEL assay), and by sperm concentrations. The female body weight increased in jet fuel group and the male body weight increased in the plastics, dioxin and jet fuel groups. Both ovary and testis weights were reduced in the plastics, dioxin and jet fuel groups. Sperm concentration was decreased in the plastics group. Females in the plastics, dioxin and jet fuel groups showed an early onset of puberty. There was increased spermatogenic cell apoptosis in testis of males from vinclozolin and jet fuel groups. Decreased ovarian primordial follicle pool size was observed for all the treatment groups and increased ovarian cyst formation was found in vinclozolin, pesticide, dioxin and jet fuel groups. Therefore, like vinclozolin, plastics, dioxin and jet fuel can also induce transgenerational inheritance of disease states (early onset of puberty, increase in body weight, reduction in gonad weight, reduction in ovarian follicle pool size and increase in spermatogenic cell apoptosis) through germ-line mediated epigenetic mechanisms. Thus each treatment is able to alter the sperm epigenome to influence the transgenerational transmission of diseases. Supported by US Department of Defense and National Institutes of Health.

Epigenetic Transgenerational Actions of Various Environmental Compounds on Pubertal Onset and Gonadal Function

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