Paternal preconception phthalate exposure alters sperm methylome and embryonic programming

Oluwayiose, Oladele A.; Marcho, Chelsea; Wu, Haotian; Houle, Emily; Krawetz, Stephen A.; Suvorov, Alexander; Mager, Jesse; Pilsner, J. Richard

doi:10.1016/j.envint.2021.106693

Cited by 32 publications

(26 citation statements)

References 73 publications

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“…The hypermethylation of genes implicated in spermatogenesis ( Hist1h2ba , Sycp1 , and Taf7l ) persisted from fetal testicular cells to adult spermatogonia, resulting in the downregulation of expression of these genes [ 76 ]. DEHP alters the sperm methylome as well as DNA methylation and gene expression in the developing embryo [ 77 ]. The fertility and reproduction of the third generation was shown to be disrupted in a sex-specific manner after ancestral prenatal exposure to DEHP.…”

Section: Endocrine-disrupting Chemicals (Edcs) Transgenerational Impactmentioning

confidence: 99%

Impact of Endocrine Disruptors upon Non-Genetic Inheritance

Montjean

Neyroud

Yéfimova

et al. 2022

IJMS

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Similar to environmental factors, EDCs (endocrine-disrupting chemicals) can influence gene expression without modifying the DNA sequence. It is commonly accepted that the transgenerational inheritance of parentally acquired traits is conveyed by epigenetic alterations also known as “epimutations”. DNA methylation, acetylation, histone modification, RNA-mediated effects and extracellular vesicle effects are the mechanisms that have been described so far to be responsible for these epimutations. They may lead to the transgenerational inheritance of diverse phenotypes in the progeny when they occur in the germ cells of an affected individual. While EDC-induced health effects have dramatically increased over the past decade, limited effects on sperm epigenetics have been described. However, there has been a gain of interest in this issue in recent years. The gametes (sperm and oocyte) represent targets for EDCs and thus a route for environmentally induced changes over several generations. This review aims at providing an overview of the epigenetic mechanisms that might be implicated in this transgenerational inheritance.

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Section: Endocrine-disrupting Chemicals (Edcs) Transgenerational Impactmentioning

confidence: 99%

Impact of Endocrine Disruptors upon Non-Genetic Inheritance

Montjean

Neyroud

Yéfimova

et al. 2022

IJMS

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“…BaP-induced changes in germ cell DNA methylation were proposed as one of the epigenetic mechanisms responsible for cross- and transgenerational phenotype transmission (reviewed in 10 ), which has been corroborated by reduced DNA methyltransferase activity upon BaP exposure in zebrafish (F0) and mice (F1), as well as altered offspring methylation profiles [ 11 , 12 ]. Furthermore, DNA methylation profiles were investigated as potential genomic markers of environmental BaP exposures and may indicate the intergenerational inheritance of phenotype impairments [ 13 , 14 ]. Therefore, the sperm methylome was assessed in the F1 generation to test the hypothesis that the sperm methylome may be predictive of phenotype impacts in the same generation and may serve as an indicator for population exposure history.…”

Section: Introductionmentioning

confidence: 99%

Assessment of parental benzo[a]pyrene exposure-induced cross-generational neurotoxicity and changes in offspring sperm DNA methylome in medaka fish

Wan

et al. 2022

Environmental Epigenetics

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Previous studies have revealed that DNA methylation changes could serve as potential genomic markers for environmental benzo[a]pyrene (BaP) exposure and intergenerational inheritance of various physiological impairments (e.g., obesity and reproductive pathologies). As a typical aromatic hydrocarbon pollutant, direct BaP exposure has been shown to induce neurotoxicity. To unravel the inheritance mechanisms of the BaP-induced bone phenotype in freshwater medaka, we conducted whole-genome bisulfite sequencing of F1 sperm and identified 776 differentially-methylated genes (DMGs). Ingenuity Pathway Analysis (IPA) revealed DMGs were significantly enriched in pathways associated with neuronal development and function. Therefore, it was hypothesized that parental BaP exposure (1 μg/L, 21 days) causes offspring neurotoxicity. Furthermore, the possibility for sperm methylation as an indicator for a neurotoxic phenotype was investigated. The F0 adult brains and F1 larvae were analyzed for BaP-induced direct and inherited toxicity. Acetylcholinesterase activity was significantly reduced in the larvae, together with decreased swimming velocity. Molecular analysis revealed that the marker genes associated with neuron development and growth (alpha1-tubulin, mbp, syn2a, shh, and gap43) as well as brain development (dlx2, otx2, and krox-20) were universally downregulated in the F1 larvae (3-days post-hatching). While parental BaP exposure at an environmentally relevant concentration could induce neurotoxicity in the developing larvae, the brain function of the exposed F0 adults was unaffected. This indicates that developmental neurotoxicity in larvae may result from impaired neuronal development and differentiation, causing delayed brain growth. The present study demonstrates that the possible adverse health effects of BaP in the environment are more extensive than currently understood. Thus, the possibility of multigenerational BaP toxicity should be included in environmental risk assessments.

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“…We identified regions in sperm bearing altered DNAme and H3K4me3 in association with DDT and p,p’ -DDE exposure that were predicted to persist in the embryo. This is a plausible route for paternally mediated epigenetic inheritance that leads to effects in offspring and is supported by exposure studies in animal models (Anway and Skinner, 2006; Lismer et al ., 2021; Ly et al ., 2017; Maurice et al ., 2021; Oluwayiose et al, 2021; Skinner et al, 2013). Of relevance are two studies of paternal DDT exposures that were associated with transgenerational alterations in sperm DNAme profiles, obesity and developmental abnormalities (Maurice et al ., 2021; Skinner et al ., 2013).…”

Section: Discussionmentioning

confidence: 99%

Exposure of Greenlandic Inuit and South African VhaVenda men to the persistent DDT metabolite is associated with an altered sperm epigenome at regions implicated in paternal epigenetic transmission and developmental disease – a cross-sectional study

Lismer

Shao

Dumargne

et al. 2022

Preprint

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BackgroundThe persistent organochlorine dichlorodiphenyltrichloroethane (DDT) is banned world-wide due to its negative health effects and persistence in the environment. It is exceptionally used as an insecticide for malaria control. Exposure occurs in regions where DDT is applied, as well as in the arctic where it’s endocrine disrupting metabolite, p,p’-dichlorodiphenyldichloroethylene (p,p’-DDE) accumulates in marine mammals and fish. DDT and p,p’-DDE exposures are linked to birth defects, infertility, cancer, and neurodevelopmental delays. Of particular concern is the potential of DDT use to impact the health of generations to come. Generational effects of toxicant exposures have been described in animal models and implicated germline epigenetic factors. Similar generational effects have been shown in epidemiological studies. Although advances in understanding the molecular mechanisms mediating this epigenetic inheritance have been made, there remain major knowledge gaps in how this occurs in humans. In animal and human models, DNA methylation (DNAme) has been implicated in paternal epigenetic effects. In animal models, histone H3K4 trimethylation (H3K4me3) has been shown to be responsive to the paternal environment and linked with epigenetic transmission to the embryo. Our objectives were to define the associations between p,p’-DDE serum levels and alterations in the sperm methylome and H3K4me3 enrichment using next generation sequencing. We aimed to compare regions of epigenomic sensitivity between geographically diverse populations with different routes and levels of exposures, and to identify interactions between altered DNAme and H3K4me3 regions. The potential for p,p’-DDE to impact the health of the next generation was explored by examining the functions of the genomic regions impacted, their roles during embryo development, and in health and disease.MethodsIn the Limpopo Province of South Africa, we recruited 247 VhaVenda South African men from 12 villages that either used indoor residual spraying with DDT for malaria control or not. We selected 49 paired blood and semen samples, from men that ranged from 18 to 32 years of age (mean 25 years). Sample inclusion was based on normal sperm counts (> 15 million/ml), normal sperm DNA fragmentation index, and testing a range of p,p’-DDE exposure levels (mean 10,462.228 ± 1,792.298 ng/ml). From a total of 193 samples, 47 Greenlandic Inuit blood and semen paired samples were selected from the biobank of the INUENDO cohort. The subjects ranged from 20 to 44 years of age (mean 31 years), were born in Greenland, and all had proven fertility. Sample selection was based on obtaining a range of p,p’-DDE exposure levels (mean 870.734 ± 134.030 ng/ml). Here we determined the molecular responses at the level of the sperm epigenome to serum p,p’-DDE levels using MethylC-Capture-seq (MCC-seq) and chromatin-immunoprecipitation followed by sequencing (ChIP-seq). We identified genomic regions with altered DNA methylation (DNAme) and differential enrichment of histone H3 lysine 4 trimethylation (H3K4me3) in sperm. We used in silico analyses to discover regions of differential methylation associated with p,p’-DDE levels that were predicted to be transmitted and persist in the embryo.ResultsAlterations in DNAme and H3K4me3 enrichment followed dose response-like trends, and we identified overlapping genomic regions with DNAme sensitivities in both populations. Altered DNAme and H3K4me3 in sperm occurred at transposable elements and regulatory regions involved in fertility, disease, development, and neurofunction. A subset of regions with altered sperm DNAme and H3K4me3 were predicted to persist in the pre-implantation embryo and were associated with embryonic gene expression.LimitationsThe samples were collected from remote areas of the world thus sample size is relatively small. The populations differed in the routes of exposure, timing of collection, mean age (mean of 25 versus 31 years of age in South African and Greenlandic populations respectively) and in the timing of p,p’-DDE measurement. Moreover, the Greenlandic Inuit men were proven fertile whereas the fertility status of the South African men was unknown. Confounding factors such as other environmental exposures and selection bias cannot be ruled out.ConclusionsThese findings suggest that in men, DDT and p,p’-DDE exposure impacts the sperm epigenome in a dose-responsive manner and may negatively impact the health of future generations through epigenetic mechanisms.

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Paternal preconception phthalate exposure alters sperm methylome and embryonic programming

Cited by 32 publications

References 73 publications

Impact of Endocrine Disruptors upon Non-Genetic Inheritance

Impact of Endocrine Disruptors upon Non-Genetic Inheritance

Assessment of parental benzo[a]pyrene exposure-induced cross-generational neurotoxicity and changes in offspring sperm DNA methylome in medaka fish

Exposure of Greenlandic Inuit and South African VhaVenda men to the persistent DDT metabolite is associated with an altered sperm epigenome at regions implicated in paternal epigenetic transmission and developmental disease – a cross-sectional study

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