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. DESCRIPTION (provided by applicant): 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES012974-09
Application #
8461236
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Chadwick, Lisa
Project Start
2004-04-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
9
Fiscal Year
2013
Total Cost
$337,522
Indirect Cost
$88,426
Name
Washington State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Skinner, Michael K; Ben Maamar, Millissia; Sadler-Riggleman, Ingrid et al. (2018) Alterations in sperm DNA methylation, non-coding RNA and histone retention associate with DDT-induced epigenetic transgenerational inheritance of disease. Epigenetics Chromatin 11:8
Gartstein, Maria A; Skinner, Michael K (2018) Prenatal influences on temperament development: The role of environmental epigenetics. Dev Psychopathol 30:1269-1303
Ben Maamar, Millissia; Sadler-Riggleman, Ingrid; Beck, Daniel et al. (2018) Epigenetic Transgenerational Inheritance of Altered Sperm Histone Retention Sites. Sci Rep 8:5308
Nilsson, Eric E; Sadler-Riggleman, Ingrid; Skinner, Michael K (2018) Environmentally induced epigenetic transgenerational inheritance of disease. Environ Epigenet 4:dvy016
Ben Maamar, Millissia; Sadler-Riggleman, Ingrid; Beck, Daniel et al. (2018) Alterations in sperm DNA methylation, non-coding RNA expression, and histone retention mediate vinclozolin-induced epigenetic transgenerational inheritance of disease. Environ Epigenet 4:dvy010
Holder, Lawrence B; Haque, M Muksitul; Skinner, Michael K (2017) Machine learning for epigenetics and future medical applications. Epigenetics 12:505-514
Beck, Daniel; Sadler-Riggleman, Ingrid; Skinner, Michael K (2017) Generational comparisons (F1 versus F3) of vinclozolin induced epigenetic transgenerational inheritance of sperm differential DNA methylation regions (epimutations) using MeDIP-Seq. Environ Epigenet 3:
McNew, Sabrina M; Beck, Daniel; Sadler-Riggleman, Ingrid et al. (2017) Epigenetic variation between urban and rural populations of Darwin's finches. BMC Evol Biol 17:183
Carvan 3rd, Michael J; Kalluvila, Thomas A; Klingler, Rebekah H et al. (2017) Mercury-induced epigenetic transgenerational inheritance of abnormal neurobehavior is correlated with sperm epimutations in zebrafish. PLoS One 12:e0176155
McBirney, Margaux; King, Stephanie E; Pappalardo, Michelle et al. (2017) Atrazine induced epigenetic transgenerational inheritance of disease, lean phenotype and sperm epimutation pathology biomarkers. PLoS One 12:e0184306

Showing the most recent 10 out of 68 publications