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

E Nilsson, Center for Reproductive Biology, Washington State University, Pullman, United States
M Anway, Center for Reproductive Biology, Washington state University, Pullman, United States
J Stanfield, Center for Reproductive Biology, Washington State University, Pullman, United States
M Skinner, Center for Reproductive Biology, Washington State University, Pullman, 99164-4231, United States

Correspondence: Michael Skinner, Email: skinner{at}mail.wsu.edu

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 to 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 of 105 pregnant rats (8.6%) from the vinclozolin F1-F3 generations exhibited uterine hemorrhage and/or anemia late in pregnancy. None (0 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 vinclozolin F2 and F3 generation adult females compared to 18% of controls. Adult female vinclozolin generation animals also developed various types of tumors in 6.5% of the animals (11 of 170), while 2% of control line animals (3 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