Dioxin (TCDD) induces epigenetic transgenerational inheritance of adult onset disease and sperm epimutations

Mohan Manikkam, Rebecca Tracey, Carlos Guerrero-Bosagna, Michael K Skinner, Mohan Manikkam, Rebecca Tracey, Carlos Guerrero-Bosagna, Michael K Skinner

Abstract

Environmental compounds can promote epigenetic transgenerational inheritance of adult-onset disease in subsequent generations following ancestral exposure during fetal gonadal sex determination. The current study examined the ability of dioxin (2,3,7,8-tetrachlorodibenzo[p]dioxin, TCDD) to promote epigenetic transgenerational inheritance of disease and DNA methylation epimutations in sperm. Gestating F0 generation females were exposed to dioxin during fetal day 8 to 14 and adult-onset disease was evaluated in F1 and F3 generation rats. The incidences of total disease and multiple disease increased in F1 and F3 generations. Prostate disease, ovarian primordial follicle loss and polycystic ovary disease were increased in F1 generation dioxin lineage. Kidney disease in males, pubertal abnormalities in females, ovarian primordial follicle loss and polycystic ovary disease were increased in F3 generation dioxin lineage animals. Analysis of the F3 generation sperm epigenome identified 50 differentially DNA methylated regions (DMR) in gene promoters. These DMR provide potential epigenetic biomarkers for transgenerational disease and ancestral environmental exposures. Observations demonstrate dioxin exposure of a gestating female promotes epigenetic transgenerational inheritance of adult onset disease and sperm epimutations.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Dioxin and control lineage F1…
Figure 1. Dioxin and control lineage F1 and F3 generation adult-onset kidney disease.
Percentages of females (panel A) and males (panel B) with kidney disease and number of diseased rats/total number of rats (*P

Figure 2. Dioxin and control lineage F1…

Figure 2. Dioxin and control lineage F1 and F3 generation pubertal abnormality and ovarian disease.

Figure 2. Dioxin and control lineage F1 and F3 generation pubertal abnormality and ovarian disease.
Percentages of females (panel A) and males (panel B) with pubertal abnormality, or primordial follicle loss (panel C), or polycystic ovary disease (panel D), or those with tumor development (panels E and F). The number of diseased rats/total number of rats in each lineage are presented (*P

Figure 3. Dioxin and control lineage F1…

Figure 3. Dioxin and control lineage F1 and F3 generation adult-onset transgenerational testis or prostate…

Figure 3. Dioxin and control lineage F1 and F3 generation adult-onset transgenerational testis or prostate disease.
Percentages of males with testis (panel A) or prostate disease (panel B) and number of diseased rats/total number of rats (***P

Figure 4. Dioxin and control lineage F1…

Figure 4. Dioxin and control lineage F1 and F3 generation adult-onset diseases in rats.

Incidences…

Figure 4. Dioxin and control lineage F1 and F3 generation adult-onset diseases in rats.
Incidences of total female disease (panel A), total male disease (panel B), female multiple disease (panel C) and male multiple disease (panel D) and number of diseased rats/total number of rats (*P

Figure 5. Dioxin promoted F3 generation sperm…

Figure 5. Dioxin promoted F3 generation sperm epimutations.

Chromosomal locations for transgenerational differential DNA methylation…

Figure 5. Dioxin promoted F3 generation sperm epimutations.
Chromosomal locations for transgenerational differential DNA methylation regions (DMR) (arrowheads). There were 50 DMR in sperm DNA from dioxin lineage rats compared to control lineage rats.

Figure 6. Dioxin induced DMR and functional…

Figure 6. Dioxin induced DMR and functional gene categories.

Number of DMR associated with various…

Figure 6. Dioxin induced DMR and functional gene categories.
Number of DMR associated with various gene categories.

Figure 7. Gene network of DMR associated…

Figure 7. Gene network of DMR associated genes.

The DMR associated genes with connections to…

Figure 7. Gene network of DMR associated genes.
The DMR associated genes with connections to various cellular processes and associated cellular localization.
All figures (7)
Similar articles
Cited by
References
    1. Skinner MK, Manikkam M, Guerrero-Bosagna C (2010) Epigenetic transgenerational actions of environmental factors in disease etiology. Trends Endocrinol Metab 21: 214–222. - PMC - PubMed
    1. Anway MD, Cupp AS, Uzumcu M, Skinner MK (2005) Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308: 1466–1469. - PubMed
    1. Reik W, Dean W, Walter J (2001) Epigenetic reprogramming in mammalian development. Science 293: 1089–1093. - PubMed
    1. Guerrero-Bosagna C, Settles M, Lucker B, Skinner M (2010) Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome. PLoS ONE 5: e13100. - PMC - PubMed
    1. Manikkam M, Guerrero-Bosagna C, Tracey R, Haque MM, Skinner MK (2012) Transgenerational Actions of Environmental Compounds on Reproductive Disease and Epigenetic Biomarkers of Ancestral Exposures. PLoS ONE 7: e31901. - PMC - PubMed
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Financial support of the USA Department of Defense (DOD) and NIH, NIEHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Figure 2. Dioxin and control lineage F1…
Figure 2. Dioxin and control lineage F1 and F3 generation pubertal abnormality and ovarian disease.
Percentages of females (panel A) and males (panel B) with pubertal abnormality, or primordial follicle loss (panel C), or polycystic ovary disease (panel D), or those with tumor development (panels E and F). The number of diseased rats/total number of rats in each lineage are presented (*P

Figure 3. Dioxin and control lineage F1…

Figure 3. Dioxin and control lineage F1 and F3 generation adult-onset transgenerational testis or prostate…

Figure 3. Dioxin and control lineage F1 and F3 generation adult-onset transgenerational testis or prostate disease.
Percentages of males with testis (panel A) or prostate disease (panel B) and number of diseased rats/total number of rats (***P

Figure 4. Dioxin and control lineage F1…

Figure 4. Dioxin and control lineage F1 and F3 generation adult-onset diseases in rats.

Incidences…

Figure 4. Dioxin and control lineage F1 and F3 generation adult-onset diseases in rats.
Incidences of total female disease (panel A), total male disease (panel B), female multiple disease (panel C) and male multiple disease (panel D) and number of diseased rats/total number of rats (*P

Figure 5. Dioxin promoted F3 generation sperm…

Figure 5. Dioxin promoted F3 generation sperm epimutations.

Chromosomal locations for transgenerational differential DNA methylation…

Figure 5. Dioxin promoted F3 generation sperm epimutations.
Chromosomal locations for transgenerational differential DNA methylation regions (DMR) (arrowheads). There were 50 DMR in sperm DNA from dioxin lineage rats compared to control lineage rats.

Figure 6. Dioxin induced DMR and functional…

Figure 6. Dioxin induced DMR and functional gene categories.

Number of DMR associated with various…

Figure 6. Dioxin induced DMR and functional gene categories.
Number of DMR associated with various gene categories.

Figure 7. Gene network of DMR associated…

Figure 7. Gene network of DMR associated genes.

The DMR associated genes with connections to…

Figure 7. Gene network of DMR associated genes.
The DMR associated genes with connections to various cellular processes and associated cellular localization.
All figures (7)
Similar articles
Cited by
References
    1. Skinner MK, Manikkam M, Guerrero-Bosagna C (2010) Epigenetic transgenerational actions of environmental factors in disease etiology. Trends Endocrinol Metab 21: 214–222. - PMC - PubMed
    1. Anway MD, Cupp AS, Uzumcu M, Skinner MK (2005) Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308: 1466–1469. - PubMed
    1. Reik W, Dean W, Walter J (2001) Epigenetic reprogramming in mammalian development. Science 293: 1089–1093. - PubMed
    1. Guerrero-Bosagna C, Settles M, Lucker B, Skinner M (2010) Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome. PLoS ONE 5: e13100. - PMC - PubMed
    1. Manikkam M, Guerrero-Bosagna C, Tracey R, Haque MM, Skinner MK (2012) Transgenerational Actions of Environmental Compounds on Reproductive Disease and Epigenetic Biomarkers of Ancestral Exposures. PLoS ONE 7: e31901. - PMC - PubMed
Show all 73 references
Publication types
MeSH terms
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Grant support
Financial support of the USA Department of Defense (DOD) and NIH, NIEHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Figure 3. Dioxin and control lineage F1…
Figure 3. Dioxin and control lineage F1 and F3 generation adult-onset transgenerational testis or prostate disease.
Percentages of males with testis (panel A) or prostate disease (panel B) and number of diseased rats/total number of rats (***P

Figure 4. Dioxin and control lineage F1…

Figure 4. Dioxin and control lineage F1 and F3 generation adult-onset diseases in rats.

Incidences…

Figure 4. Dioxin and control lineage F1 and F3 generation adult-onset diseases in rats.
Incidences of total female disease (panel A), total male disease (panel B), female multiple disease (panel C) and male multiple disease (panel D) and number of diseased rats/total number of rats (*P

Figure 5. Dioxin promoted F3 generation sperm…

Figure 5. Dioxin promoted F3 generation sperm epimutations.

Chromosomal locations for transgenerational differential DNA methylation…

Figure 5. Dioxin promoted F3 generation sperm epimutations.
Chromosomal locations for transgenerational differential DNA methylation regions (DMR) (arrowheads). There were 50 DMR in sperm DNA from dioxin lineage rats compared to control lineage rats.

Figure 6. Dioxin induced DMR and functional…

Figure 6. Dioxin induced DMR and functional gene categories.

Number of DMR associated with various…

Figure 6. Dioxin induced DMR and functional gene categories.
Number of DMR associated with various gene categories.

Figure 7. Gene network of DMR associated…

Figure 7. Gene network of DMR associated genes.

The DMR associated genes with connections to…

Figure 7. Gene network of DMR associated genes.
The DMR associated genes with connections to various cellular processes and associated cellular localization.
All figures (7)
Similar articles
Cited by
References
    1. Skinner MK, Manikkam M, Guerrero-Bosagna C (2010) Epigenetic transgenerational actions of environmental factors in disease etiology. Trends Endocrinol Metab 21: 214–222. - PMC - PubMed
    1. Anway MD, Cupp AS, Uzumcu M, Skinner MK (2005) Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308: 1466–1469. - PubMed
    1. Reik W, Dean W, Walter J (2001) Epigenetic reprogramming in mammalian development. Science 293: 1089–1093. - PubMed
    1. Guerrero-Bosagna C, Settles M, Lucker B, Skinner M (2010) Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome. PLoS ONE 5: e13100. - PMC - PubMed
    1. Manikkam M, Guerrero-Bosagna C, Tracey R, Haque MM, Skinner MK (2012) Transgenerational Actions of Environmental Compounds on Reproductive Disease and Epigenetic Biomarkers of Ancestral Exposures. PLoS ONE 7: e31901. - PMC - PubMed
Show all 73 references
Publication types
MeSH terms
Substances
Grant support
Financial support of the USA Department of Defense (DOD) and NIH, NIEHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Figure 4. Dioxin and control lineage F1…
Figure 4. Dioxin and control lineage F1 and F3 generation adult-onset diseases in rats.
Incidences of total female disease (panel A), total male disease (panel B), female multiple disease (panel C) and male multiple disease (panel D) and number of diseased rats/total number of rats (*P

Figure 5. Dioxin promoted F3 generation sperm…

Figure 5. Dioxin promoted F3 generation sperm epimutations.

Chromosomal locations for transgenerational differential DNA methylation…

Figure 5. Dioxin promoted F3 generation sperm epimutations.
Chromosomal locations for transgenerational differential DNA methylation regions (DMR) (arrowheads). There were 50 DMR in sperm DNA from dioxin lineage rats compared to control lineage rats.

Figure 6. Dioxin induced DMR and functional…

Figure 6. Dioxin induced DMR and functional gene categories.

Number of DMR associated with various…

Figure 6. Dioxin induced DMR and functional gene categories.
Number of DMR associated with various gene categories.

Figure 7. Gene network of DMR associated…

Figure 7. Gene network of DMR associated genes.

The DMR associated genes with connections to…

Figure 7. Gene network of DMR associated genes.
The DMR associated genes with connections to various cellular processes and associated cellular localization.
All figures (7)
Figure 5. Dioxin promoted F3 generation sperm…
Figure 5. Dioxin promoted F3 generation sperm epimutations.
Chromosomal locations for transgenerational differential DNA methylation regions (DMR) (arrowheads). There were 50 DMR in sperm DNA from dioxin lineage rats compared to control lineage rats.
Figure 6. Dioxin induced DMR and functional…
Figure 6. Dioxin induced DMR and functional gene categories.
Number of DMR associated with various gene categories.
Figure 7. Gene network of DMR associated…
Figure 7. Gene network of DMR associated genes.
The DMR associated genes with connections to various cellular processes and associated cellular localization.

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Drug Interventions

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