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. 2019 May 27;5(2):dvz008.
doi: 10.1093/eep/dvz008. eCollection 2019 Apr.

Sperm Epimutation Biomarkers of Obesity and Pathologies Following DDT Induced Epigenetic Transgenerational Inheritance of Disease

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Free PMC article

Sperm Epimutation Biomarkers of Obesity and Pathologies Following DDT Induced Epigenetic Transgenerational Inheritance of Disease

Stephanie E King et al. Environ Epigenet. .
Free PMC article

Abstract

Dichlorodiphenyltrichloroethane (DDT) has previously been shown to promote the epigenetic transgenerational inheritance of adult onset disease in rats. The current study investigated the potential that sperm epimutation biomarkers can be used to identify ancestral induced transgenerational obesity and associated pathologies. Gestating F0 generational female rats were transiently exposed to DDT during fetal gonadal sex determination, and the incidence of adult-onset pathologies was assessed in the subsequent F1, F2, and F3 generations. In addition, sperm differential DNA methylation regions (DMRs) that were associated with specific pathologies in the transgenerational F3 generation males were investigated. There was an increase of testis disease and early-onset puberty in the F2 generation DDT lineage males. The F3 generation males and females had significant increases in the incidence of obesity and multiple disease. The F3 generation DDT males also had significant increases in testis disease, prostate disease, and late onset puberty. The F3 generation DDT females had increases in ovarian and kidney disease. Epigenetic alterations of the germline are required for the transgenerational inheritance of pathology. Therefore, the F3 generation sperm was collected to examine DMRs for the ancestrally exposed DDT male population. Unique sets of DMRs were associated with late onset puberty, prostate disease, kidney disease, testis disease, obesity, and multiple disease pathologies. Gene associations with the DMR were also identified. The epigenetic DMR signatures identified for these pathologies provide potential biomarkers for transgenerationally inherited disease susceptibility.

Keywords: DDT; DNA methylation; diagnostics; epigenetics; obesity; transgenerational.

Figures

Figure 1:
Figure 1:
pathology analysis in F1, F2, and F3 generation control and DDT lineage 1-year-old male rats. (A) Testis disease frequency, (B) prostate disease frequency, (C) male kidney disease frequency, (D) average age at puberty for males, (E) tumor frequency in males, (F) male obesity frequency, and (G) multiple disease. The pathology number ratio with total animal number is listed for each bar graph (A–G), statistical significance is represented with the P-value indicated (*P <0.05; **P <0.01; ***P <0.001)
Figure 2:
Figure 2:
pathology analysis in F1, F2, and F3 generation control and DDT lineage 1-year-old female rats. (A) Ovary disease frequency, (B) average age at puberty for females, (C) female kidney disease frequency, (D) tumor disease frequency, (E) female obesity frequency, and (F) multiple disease. The pathology number ratio with total animal number is listed for each bar graph (A–F), statistical significance is represented with the P-value indicated (*P <0.05; **P <0.01; ***P <0.001)
Figure 3:
Figure 3:
disease-specific DMR analysis. The number of DMRs found using different P-value cutoff thresholds are presented. The All Window column shows all DMRs. The Multiple Window column shows the number of DMRs containing at least two significant windows. The number of DMRs with each specific number of significant windows is shown: (A) late puberty, (B) prostate disease, (C) kidney disease, (D) testis disease, (E) obesity, and (F) multiple disease
Figure 4:
Figure 4:
chromosomal locations of disease-specific DMRs. DMR locations on the individual chromosomes are presented. (A) Late puberty, all DMRs at a P-value threshold of 1e-08 are shown. (B) Prostate disease, all DMRs at a P-value threshold of 1e-05 are shown. (C) Kidney disease, all DMRs at a P-value threshold of 1e-07 are shown. (D) Testis disease, all DMRs at a P-value threshold of 1e-05 are shown. (E) Obesity, all DMRs at a P-value threshold of 1e-05 are shown. (F) Multiple disease, all DMRs at a P-value threshold of 1e-05 are shown. The red arrowhead indicates the DMR location and black box a cluster of DMRs
Figure 5:
Figure 5:
DMR overlap Venn diagram for specific disease DMRs. (A) The overlaps for specific diseases and (B) overlaps with multiple disease are presented
Figure 6:
Figure 6:
DMR gene associations. (A) DMR-associated gene functional categories (genes within 10-kb DMR). (B) KEGG pathways containing DMR-associated genes. Number of DMR-associated genes in pathway is provided in brackets. Pathways in bold are common to at least two pathology DMR sets

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