Transgenerational effects of environmental factors, such as pesticides, plastics and fungicides, significantly amplify the impact and health hazards of these compounds. The transgenerational actions of these compounds require a heritable epigenetic alteration of the germline. This transgenerational epigenetic phenomenon is anticipated to be an important aspect of adult onset disease etiology, and suggests ancestral environmental exposure may influence disease epidemiology. The current proposal is designed to investigate this transgenerational phenomenon and the underlying epigenetic mechanism(s) involved. The model endocrine disruptor utilized will be the fungicide vinclozolin, an anti-androgenic compound, studied in an outbred rodent (i.e. rat) system. Previously, we demonstrated that vinclozolin exposure during embryonic gonadal sex determination promotes an epigenetic reprogramming of the male germline that then induces transgenerational adult onset disease states of male infertility, prostate disease, kidney disease, immune abnormalities and tumor development. The objective of the current proposal is to provide further insights into the molecular, cellular and physiological (i.e. systems biology) actions of this endocrine disruptor on the induction of this transgenerational epigenetic phenomenon. The overall hypothesis to be tested is that transient in utero exposure to the endocrine disruptor vinclozolin promotes a permanent reprogramming of the epigenome (i.e. DNA methylation) of the male germ line that then, through alterations in critical epigenetic regulatory mechanism(s), transgenerationally promotes adult onset disease (e.g. male infertility). Previous studies have shown a transgenerational epigenetic effect on the male germ line (sperm) through alterations in DNA methylation. This epigenetic alteration in the germ line is proposed to subsequently promote transgenerational effects on the epigenomes and transcriptomes of numerous organ systems in the adult. The current proposal is designed to further investigate these transgenerational epigenetic effects on the male germ line to determine the functional relationship with the induction of specific adult onset disease states, and to reveal the underlying epigenetic mechanisms responsible for this phenomenon. The experimental approach to test the above hypothesis consists of the following specific aims: 1) Investigate the transgenerational actions of vinclozolin on the sperm epigenome (DNA methylation) to identify genome-wide epigenetic biomarkers. 2) Characterize the direct and transgenerational effects of vinclozolin exposure on the fetal male germ cell epigenome and transcriptome. 3) Correlate the sperm epigenetic biomarkers with transgenerational adult onset disease phenotypes, and investigate the potential role of the biomarkers in the dysregulation of adult somatic tissue transcriptomes associated with specific disease states. Completion of the proposed research will determine how environmental exposures and compounds may promote adult onset disease in a transgenerational manner. The epigenetic biomarkers associated with the epigenetic reprogramming of the male germ line will be identified. The potential role these biomarkers may have in newly created epigenetic control regions (ECR) to promote transgenerational dysregulation of tissue transcriptomes will be established and provide insight into the etiology of adult onset disease. The potential for epigenetic biomarkers to be used as early stage diagnostic markers for specific adult onset disease states will also be established. The proposed research will more thoroughly investigate this epigenetic transgenerational phenomenon and elucidate the molecular mechanisms involved.

Public Health Relevance

The proposed research will be used to extrapolate and provide insights into the potential impact of environmental exposures on human development, reproduction and health. The novel observations involving a transgenerational epigenetic element of disease etiology critically impacts the potential hazards of environmental compounds. The proposed research will more thoroughly investigate this phenomenon and elucidate the molecular mechanisms involved.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Chadwick, Lisa
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Washington State University
Schools of Arts and Sciences
United States
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Schuster, Andrew; Skinner, Michael K; Yan, Wei (2016) Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs. Environ Epigenet 2:
Skinner, Michael K (2016) Endocrine disruptors in 2015: Epigenetic transgenerational inheritance. Nat Rev Endocrinol 12:68-70
Skinner, Michael K (2016) Differential DNA methylation analysis optimally requires purified cell populations. Fertil Steril 106:551
Hanson, Mark A; Skinner, Michael K (2016) Developmental origins of epigenetic transgenerational inheritance. Environ Epigenet 2:
Guillette Jr, Louis J; Parrott, Benjamin B; Nilsson, Eric et al. (2016) Epigenetic programming alterations in alligators from environmentally contaminated lakes. Gen Comp Endocrinol :
Gillette, Ross; Miller-Crews, Isaac; Skinner, Michael K et al. (2015) Distinct actions of ancestral vinclozolin and juvenile stress on neural gene expression in the male rat. Front Genet 6:56
Nilsson, Eric E; Skinner, Michael K (2015) Environmentally Induced Epigenetic Transgenerational Inheritance of Reproductive Disease. Biol Reprod 93:145
Skinner, Michael K; Bhandari, Ramji K; Haque, M Muksitul et al. (2015) Environmentally Induced Epigenetic Transgenerational Inheritance of Altered SRY Genomic Binding During Gonadal Sex Determination. Environ Epigenet 1:dvv004
Haque, M Muksitul; Holder, Lawrence B; Skinner, Michael K (2015) Genome-Wide Locations of Potential Epimutations Associated with Environmentally Induced Epigenetic Transgenerational Inheritance of Disease Using a Sequential Machine Learning Prediction Approach. PLoS One 10:e0142274
Nilsson, Eric E; Skinner, Michael K (2015) Environmentally induced epigenetic transgenerational inheritance of disease susceptibility. Transl Res 165:12-7

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