Transgenerational epigenetic effects of the endocrine disruptor vinclozolin on pregnancies and female adult onset disease

Abstract

Endocrine disruptor exposure during gonadal sex determination was previously found to induce male rat adult onset transgenerational disease (F1-F4 generation), and this was associated with an alteration in the epigenetic (i.e., DNA methylation) programming of the male germ line. The current study was designed to characterize the transgenerational disease phenotypes of the female adult offspring. Pregnant rats (F0 generation) were treated transiently with vinclozolin (i.e., fungicide with anti-androgenic activity) on embryonic (E) days E8-E14 of gestation. F1 control and vinclozolin generation offspring from different litters were mated to produce F2 offspring, and similarly F2 generation animals produced F3 generation offspring. Observations demonstrated that 9 out of 105 pregnant rats (8.6%) from the vinclozolin F1-F3 generations exhibited uterine hemorrhage and/or anemia late in pregnancy. None (0 out of 82) of the control F1-F3 generation females had similar pregnancy problems. Complete blood cell counts and serum chemistry profiles demonstrated that selected vinclozolin generation animals, but not controls, exhibited marked regenerative anemia in late pregnancy. Examination of kidney histology revealed moderate or severe glomerular abnormalities in 67% of the vinclozolin F2 and F3 generation adult females compared with 18% of the controls. Adult female vinclozolin generation animals also developed various types of tumors in 6.5% of the animals (11 out of 170), while 2% of control-line animals (3 out of 151) developed mammary tumors. Observations demonstrate that vinclozolin exposure during gonadal sex determination promotes a transgenerational increase in pregnancy abnormalities and female adult onset disease states.

The effects of methyl-donor deficiency on mutation induction and transgenerational instability in mice

“…These data imply that the passive erasure of epigenetic marks in the maternal genome can diminish the transgenerational effects of foetal irradiation, while the active demethylation of the paternal genome may preserve more epigenetic modifications than the passive process occurring in the maternal pronucleus (Barber et al, 2009). This hypothesis is consistent with the results of several other studies showing transgenerational effects of prenatal exposure to the endocrine disruptor vinclozolin, where transmission was observed exclusively through the male germline (Anway et al, 2005;Nilsson et al, 2008).…”

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 sperm-positive (day 0) rats were monitored for diestrus and changes in body weight. If pregnant, then on days 8 through 14 of gestation [58], the females were administered daily intraperitoneal injections of vinclozolin (100 mg/kg BW/day, Chem Services, Westchester, PA), DDT (dichloro-diphenyl-trichloroethane) (25 mg/kg BW/day, Chem Services), or dimethyl sulfoxide (vehicle) as previously described [42]. Treatment groups were designated ‘vinclozolin’, ‘DDT’ and ‘control’ lineages.…”

Timing is everything

“…32 Female rats exposed to vinclozolin during gestation produce male offspring with methylation changes in numerous genes in their sperm and female offspring with a greater incidence of tumor formation and pregnancy abnormalities. [33][34][35] Because F1 and F2 germ cells are present in the exposed gestating female, these cells were therefore also exposed to vinclozolin during early development and indeed, these effects persist even transgenerationally. Bisphenol A (BPA), a widely studied endocrine disruptor, is ubiquitous in our environment and has been repeatedly shown to affect DNA methylation in multiple rodent tissues such as liver and brain.…”