Alterations in sperm DNA methylation, non-coding RNA and histone retention associate with DDT-induced epigenetic transgenerational inheritance of disease

Skinner, Michael K.; Maamar, Millissia Ben; Sadler‐Riggleman, Ingrid; Beck, Daniel; Nilsson, Eric; McBirney, Margaux; Klukovich, Rachel; Xie, Yeming; Tang, Chong; Yan, Wei

doi:10.1186/s13072-018-0178-0

Cited by 166 publications

(167 citation statements)

References 78 publications

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“…, there are data for transgenerational inheritance of diseases/dysfunctions including reproduction, obesity, psychiatric disorders from a variety of environmental stressors including vinclozolin, bisphenol A, atrazine bisphenol A plus phthalates (DEHP and DBP), permethrin plus DEET, methoxychlor, Jet fuel 8, phthalate (DEHP),dioxin, DDT, PCBs, tributyltin, nicotine, alcohol, calorie restriction, high‐fat diets, folate and stress. Mechanisms currently focus on a variety of epigenetic changes including DNA methylation, histone changes and non‐coding RNAs . Alterations in germ cells are required to transmit epigenetic information to future generations.…”

Section: Transgenerational Inheritancementioning

confidence: 99%

“…Nonetheless, the consensus is that transgenerational inheritance does exist for a growing list of environmental stressors. 21 Thus, it is essential to understand the importance of transgenerational inheritance of disease outcomes to the increasing incidence of many important human diseases. As shown in Figure 1, transgenerational inheritance results in the transmission of diseases to future generations from exposure to a single generation.…”

Section: Transgenerational Inheritancementioning

confidence: 99%

“…Mechanisms currently focus on a variety of epigenetic changes including DNA methylation, histone changes and non-coding RNAs. 21,27 Alterations in germ cells are required to transmit epigenetic information to future generations. Recent findings indicate that sperm are not that much different from somatic cells, in that they contain chromatin with modified histones in a three-dimensional architecture, some non-methylated DNA sites in promoter regions and promoters and enhancers in a primed state 27 and nc RNAs.…”

Section: Transgenerational Inheritancementioning

confidence: 99%

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The developmental basis of disease: Update on environmental exposures and animal models

Heindel

2018

Basic Clin Pharma Tox

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At the Prenatal Programming and Toxicity (PPTox) Conference I in 2008, I presented an overview of the developmental origins of health and disease field focusing on environmental chemical exposures and disease outcomes. At that time, I noted that the field was getting off the ground with a focus on developmental exposure to a small number of endocrine disrupting chemicals (EDCs) and disease outcomes across the lifespan in animal models. In this update, I note that the DOHaD field has changed significantly over the last decade. There are new windows of susceptibility including preconception, prepuberty, a focus on the mother and not just the offspring, and a significant focus on the new field of epigenetic transgenerational inheritance. New disease focus areas have sprung up including obesity, type 2 diabetes and fatty liver disease, all with a connection to developmental exposures to EDCs. There is also a focus on the study of new EDCs, molecular mechanisms, the development of new biomarkers of exposure and disease outcomes and studies focusing on intervention and prevention studies.

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Section: Transgenerational Inheritancementioning

confidence: 99%

Section: Transgenerational Inheritancementioning

confidence: 99%

Section: Transgenerational Inheritancementioning

confidence: 99%

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The developmental basis of disease: Update on environmental exposures and animal models

Heindel

2018

Basic Clin Pharma Tox

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“…The mode of transportation of RNAs may be via membrane-bound vesicles that are expelled from cells and contain an abundance of small RNAs [15][16][17], including miRNAs [18]. Long non-coding RNAs have also been indirectly postulated to be transferred to offspring due to experience-dependent alterations in the sperm [19][20][21][22]. We, therefore, postulated that somatically expressed RNAs may be transported to the germline allowing real-time heritability of somatic, experience-dependent alterations.…”

Section: Introductionmentioning

confidence: 99%

Direct evidence for transport of RNA from the mouse brain to the germline and offspring

O’Brien

Ensbey

Day

et al. 2019

Preprint

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AbstractBackgroundThe traditional concept that heritability occurs exclusively from the transfer of germline-restricted genetics is being challenged by the increasing accumulation of evidence confirming the existence of experience-dependent transgenerational inheritance. However, questions remain unanswered as to how heritable information can be passed from somatic cells. Previous studies have implicated the critical involvement of RNA in heritable transgenerational effects and the high degree of mobility and genomic impact of RNAs in all organisms is an attractive model for the efficient transfer of genetic information.ResultsWe hypothesized that RNA may be transported from a somatic tissue, in this case the brain, of an adult male mouse to the germline, and subsequently to offspring. To investigate this, we injected one hemisphere of the male mouse striatum with an AAV1/9 virus expressing human pre-MIR941 (MIR941). After 2, 8 and 16 weeks following injection, we used an LNA-based qPCR system to detect the presence of virus and human MIR941 in brain, peripheral tissues and offspring, from injected male mice mated with uninjected females. Virus was never detected outside of the brain. Verification of single bands of the correct size for MIR941 was performed using Sanger sequencing while quantitation demonstrated that a small percentage (∼ 1-8%) of MIR941 is transported to the germline and to offspring in about a third of the cases.ConclusionsWe show that somatic RNA can be transported to the germline and passed on to offspring, thereby providing additional evidence of a role for RNA in somatic cell-derived transgenerational effects.

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“…Small noncoding RNAs are known to regulate gene expression by affecting transcript stability and have been shown to be abundant in sperm with a single spermatozoon containing above 20,000 long and short noncoding RNAs [21,22]. Recently, concurrent alterations of DNA methylation, ncRNA, and histone alterations have been identified in sperm mediating the epigenetic transgenerational inheritance of pathology [23,24]. Therefore, the current study investigates alterations in both DNA methylation, ncRNA expression and gene expression.…”

Section: Introductionmentioning

confidence: 99%

Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency

et al. 2018

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Two of the most prevalent ovarian diseases affecting women’s fertility and health are Primary Ovarian Insufficiency (POI) and Polycystic Ovarian Syndrome (PCOS). Previous studies have shown that exposure to a number of environmental toxicants can promote the epigenetic transgenerational inheritance of ovarian disease. In the current study, transgenerational changes to the transcriptome and epigenome of ovarian granulosa cells are characterized in F3 generation rats after ancestral vinclozolin or DDT exposures. In purified granulosa cells from 20-day-old F3 generation females, 164 differentially methylated regions (DMRs) (P < 1 x 10−6) were found in the F3 generation vinclozolin lineage and 293 DMRs (P < 1 x 10−6) in the DDT lineage, compared to controls. Long noncoding RNAs (lncRNAs) and small noncoding RNAs (sncRNAs) were found to be differentially expressed in both the vinclozolin and DDT lineage granulosa cells. There were 492 sncRNAs (P < 1 x 10−4) in the vinclozolin lineage and 1,085 sncRNAs (P < 1 x 10−4) in the DDT lineage. There were 123 lncRNAs and 51 lncRNAs in the vinclozolin and DDT lineages, respectively (P < 1 x 10−4). Differentially expressed mRNAs were also found in the vinclozolin lineage (174 mRNAs at P < 1 x 10−4) and the DDT lineage (212 mRNAs at P < 1 x 10−4) granulosa cells. Comparisons with known ovarian disease associated genes were made. These transgenerational epigenetic changes appear to contribute to the dysregulation of the ovary and disease susceptibility that can occur in later life. Observations suggest that ancestral exposure to toxicants is a risk factor that must be considered in the molecular etiology of ovarian disease.

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Alterations in sperm DNA methylation, non-coding RNA and histone retention associate with DDT-induced epigenetic transgenerational inheritance of disease

Cited by 166 publications

References 78 publications

The developmental basis of disease: Update on environmental exposures and animal models

The developmental basis of disease: Update on environmental exposures and animal models

Direct evidence for transport of RNA from the mouse brain to the germline and offspring

Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency

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