Environmental induced transgenerational inheritance impacts systems epigenetics in disease etiology

Abstract

Environmental toxicants have been shown to promote the epigenetic transgenerational inheritance of disease through exposure specific epigenetic alterations in the germline. The current study examines the actions of hydrocarbon jet fuel, dioxin, pesticides (permethrin and methoxychlor), plastics, and herbicides (glyphosate and atrazine) in the promotion of transgenerational disease in the great grand-offspring rats that correlates with specific disease associated differential DNA methylation regions (DMRs). The transgenerational disease observed was similar for all exposures and includes pathologies of the kidney, prostate, and testis, pubertal abnormalities, and obesity. The disease specific DMRs in sperm were exposure specific for each pathology with negligible overlap. Therefore, for each disease the DMRs and associated genes were distinct for each exposure generational lineage. Observations suggest a large number of DMRs and associated genes are involved in a specific pathology, and various environmental exposures influence unique subsets of DMRs and genes to promote the transgenerational developmental origins of disease susceptibility later in life. A novel multiscale systems biology basis of disease etiology is proposed involving an integration of environmental epigenetics, genetics and generational toxicology.

Figure 1

Exposure specific DMRs. (A) Exposure DMRs at using a p < 1e−6 edgeR p value threshold for everything except glyphosate at p < 1e−4. (B) Overlap of Exposure DMRs (p < 1e−06), *except glyphosate at p < 1e−04. (C) Extended Overlap of Exposure DMRs. The overlapping DMRs and percent overlap are indicated.

Figure 2

Specific disease DMRs. (A) Kidney disease; (B) Prostate disease; (C) Puberty pathology; (D) Testis disease; (E) Obesity; (F) Multiple pathology. The exposure, p value and number of DMR are presented. Venn diagram overlaps for each exposure DMR set are shown for (G) Kidney; (H) Prostate; (I) Puberty; (J) Testis; (K) Obesity; (L) Multiple.

Figure 3

Extended disease specific DMR overlap at p < 1e−04 versus p < 0.05. (A) Kidney; (B) Prostate; (C) Puberty; (D) Testis; (E) Obesity; (F) Multiple. The DMR number and percentage overlap presented. The horizontal row overlap identifies DMR number and percentage for each exposure.

Figure 4

Weighted co-expression network analysis WGCNA module-trait relationships. Module colors and genomic window numbers listed correlate to specific diseases and exposures. The Correlation Coefficient and p value (brackets) for each presented. Black outline correlations used for subsequent analysis.

Figure 5

Exposure DMR associated pathology genes. Pathologies and specific number of DMR per exposure: (A) Kidney; (B) Prostate; (C) Puberty; (D) Testis; (E) Obesity; (F) Multiple. Module disease associated genes; (G) Kidney disease module associated genes; (H) Prostate disease module associated genes; (I) Puberty disease module associated genes; (J) Testis disease module associated genes; (K) Obesity disease module associated genes. (L) Multiple disease module associated genes.

Figure 6

Kidney disease DMR associated genes and network. The index presents the color and exposure group for DMR associated genes. The disease pathways and processes with gene links identified.

Figure 7

Novel disease etiology paradigm. (A) Genetic determination disease etiology paradigm. (B) Environmental epigenetics and genetic disease etiology paradigm. Environmental exposures promote subsets of distinct subsets of DMR associated sites that are associated with subsets of DMR linked genes that when altered promote disease etiology and phenotypic variation. The subsets of altered epimutations are transmitted to subsequent generations through the germline to promote generational toxicology.