Pub Date : 2019-12-06eCollection Date: 2019-10-01DOI: 10.1093/eep/dvz023
G T Mørkve Knudsen, F I Rezwan, A Johannessen, S M Skulstad, R J Bertelsen, F G Real, S Krauss-Etschmann, V Patil, D Jarvis, S H Arshad, J W Holloway, C Svanes
Epidemiological studies suggest that father's smoking might influence their future children's health, but few studies have addressed whether paternal line effects might be related to altered DNA methylation patterns in the offspring. To investigate a potential association between fathers' smoking exposures and offspring DNA methylation using epigenome-wide association studies. We used data from 195 males and females (11-54 years) participating in two population-based cohorts. DNA methylation was quantified in whole blood using Illumina Infinium MethylationEPIC Beadchip. Comb-p was used to analyse differentially methylated regions (DMRs). Robust multivariate linear models, adjusted for personal/maternal smoking and cell-type proportion, were used to analyse offspring differentially associated probes (DMPs) related to paternal smoking. In sensitivity analyses, we adjusted for socio-economic position and clustering by family. Adjustment for inflation was based on estimation of the empirical null distribution in BACON. Enrichment and pathway analyses were performed on genes annotated to cytosine-phosphate-guanine (CpG) sites using the gometh function in missMethyl. We identified six significant DMRs (Sidak-corrected P values: 0.0006-0.0173), associated with paternal smoking, annotated to genes involved in innate and adaptive immunity, fatty acid synthesis, development and function of neuronal systems and cellular processes. DMP analysis identified 33 CpGs [false discovery rate (FDR) < 0.05]. Following adjustment for genomic control (λ = 1.462), no DMPs remained epigenome-wide significant (FDR < 0.05). This hypothesis-generating study found that fathers' smoking was associated with differential methylation in their adolescent and adult offspring. Future studies are needed to explore the intriguing hypothesis that fathers' exposures might persistently modify their future offspring's epigenome.
{"title":"Epigenome-wide association of father's smoking with offspring DNA methylation: a hypothesis-generating study.","authors":"G T Mørkve Knudsen, F I Rezwan, A Johannessen, S M Skulstad, R J Bertelsen, F G Real, S Krauss-Etschmann, V Patil, D Jarvis, S H Arshad, J W Holloway, C Svanes","doi":"10.1093/eep/dvz023","DOIUrl":"https://doi.org/10.1093/eep/dvz023","url":null,"abstract":"<p><p>Epidemiological studies suggest that father's smoking might influence their future children's health, but few studies have addressed whether paternal line effects might be related to altered DNA methylation patterns in the offspring. To investigate a potential association between fathers' smoking exposures and offspring DNA methylation using epigenome-wide association studies. We used data from 195 males and females (11-54 years) participating in two population-based cohorts. DNA methylation was quantified in whole blood using Illumina Infinium MethylationEPIC Beadchip. Comb-p was used to analyse differentially methylated regions (DMRs). Robust multivariate linear models, adjusted for personal/maternal smoking and cell-type proportion, were used to analyse offspring differentially associated probes (DMPs) related to paternal smoking. In sensitivity analyses, we adjusted for socio-economic position and clustering by family. Adjustment for inflation was based on estimation of the empirical null distribution in BACON. Enrichment and pathway analyses were performed on genes annotated to cytosine-phosphate-guanine (CpG) sites using the gometh function in missMethyl. We identified six significant DMRs (Sidak-corrected <i>P</i> values: 0.0006-0.0173), associated with paternal smoking, annotated to genes involved in innate and adaptive immunity, fatty acid synthesis, development and function of neuronal systems and cellular processes. DMP analysis identified 33 CpGs [false discovery rate (FDR) < 0.05]. Following adjustment for genomic control (λ = 1.462), no DMPs remained epigenome-wide significant (FDR < 0.05). This hypothesis-generating study found that fathers' smoking was associated with differential methylation in their adolescent and adult offspring. Future studies are needed to explore the intriguing hypothesis that fathers' exposures might persistently modify their future offspring's epigenome.</p>","PeriodicalId":11774,"journal":{"name":"Environmental Epigenetics","volume":"5 4","pages":"dvz023"},"PeriodicalIF":3.8,"publicationDate":"2019-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/eep/dvz023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37450074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-11-25eCollection Date: 2019-10-01DOI: 10.1093/eep/dvz021
Brittany M Hollister, Haley E Yaremych, Megan R Goldring, Susan Persky
Advances in our understanding of epigenetics present new opportunities to improve children's health through the counseling of parents about epigenetics concepts. However, it is important to first evaluate how parents respond to this type of information and determine the consequences of educating parents about epigenetics. We have taken an initial step toward this goal by assessing parental responses to an epigenetics learning module. Parents (n = 190, 126 mothers) responded to pre- and post-module survey questions. Prior to the module, parents reported that mothers' lifestyles prior to conception were more important for children's health than fathers' lifestyles prior to conception (t = 4.49, df = 316.5, P < 0.0001). However, after the module, there was no difference between ratings of the importance of mothers' and fathers' preconception lifestyles (t = 1.18, df = 319.8, P = NS). Furthermore, after viewing the module, parents increased their ratings of the importance of both mothers' (t = -5.65, df = 294.8, P < 0.0001) and father's (t = -9.01, df = 287.2, P < 0.0001) preconception lifestyles for child health. After viewing the module, most parents reported feelings of guilt and negativity regarding epigenetics (78 and 55%, respectively). When compared with lean parents, parents with overweight more often reported feelings of guilt (χ2 =10.27, P = 0.001). This work represents an important first step in evaluating parental responses to epigenetics concepts.
我们对表观遗传学的理解的进步为通过向父母咨询表观遗传学概念来改善儿童健康提供了新的机会。然而,重要的是首先要评估父母对这类信息的反应,并确定对父母进行表观遗传学教育的后果。通过评估父母对表观遗传学学习模块的反应,我们已经朝着这个目标迈出了第一步。父母(n = 190, 126名母亲)回答了模块前后的调查问题。在该模块之前,父母报告说,母亲怀孕前的生活方式比父亲怀孕前的生活方式对孩子的健康更重要(t = 4.49, df = 316.5, P < 0.0001)。然而,在模块之后,母亲和父亲的孕前生活方式的重要性评分之间没有差异(t = 1.18, df = 319.8, P = NS)。此外,在观看该模块后,父母提高了母亲(t = -5.65, df = 294.8, P < 0.0001)和父亲(t = -9.01, df = 287.2, P < 0.0001)的孕前生活方式对儿童健康的重要性。在观看了该模块后,大多数家长表示对表观遗传学感到内疚和消极(分别为78%和55%)。与瘦父母相比,超重父母更常报告有负罪感(χ 2 =10.27, P = 0.001)。这项工作是评估亲代对表观遗传学概念反应的重要的第一步。
{"title":"Mothers' and fathers' cognitive and affective responses to epigenetics concepts.","authors":"Brittany M Hollister, Haley E Yaremych, Megan R Goldring, Susan Persky","doi":"10.1093/eep/dvz021","DOIUrl":"https://doi.org/10.1093/eep/dvz021","url":null,"abstract":"<p><p>Advances in our understanding of epigenetics present new opportunities to improve children's health through the counseling of parents about epigenetics concepts. However, it is important to first evaluate how parents respond to this type of information and determine the consequences of educating parents about epigenetics. We have taken an initial step toward this goal by assessing parental responses to an epigenetics learning module. Parents (<i>n</i> = 190, 126 mothers) responded to pre- and post-module survey questions. Prior to the module, parents reported that mothers' lifestyles prior to conception were more important for children's health than fathers' lifestyles prior to conception (<i>t</i> = 4.49, df = 316.5, <i>P</i> < 0.0001). However, after the module, there was no difference between ratings of the importance of mothers' and fathers' preconception lifestyles (<i>t</i> = 1.18, df = 319.8, <i>P</i> = NS). Furthermore, after viewing the module, parents increased their ratings of the importance of both mothers' (<i>t</i> = -5.65, df = 294.8, <i>P</i> < 0.0001) and father's (<i>t</i> = -9.01, df = 287.2, <i>P</i> < 0.0001) preconception lifestyles for child health. After viewing the module, most parents reported feelings of guilt and negativity regarding epigenetics (78 and 55%, respectively). When compared with lean parents, parents with overweight more often reported feelings of guilt (<i>χ</i> <sup>2</sup> =10.27, <i>P</i> = 0.001). This work represents an important first step in evaluating parental responses to epigenetics concepts.</p>","PeriodicalId":11774,"journal":{"name":"Environmental Epigenetics","volume":"5 4","pages":"dvz021"},"PeriodicalIF":3.8,"publicationDate":"2019-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/eep/dvz021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38648759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jennifer L. M. Thorson, Mark W. Smithson, Ingrid Sadler‐Riggleman, Daniel Beck, M. Dybdahl, M. Skinner
Abstract Epigenetic variation has the potential to influence environmentally dependent development and contribute to phenotypic responses to local environments. Environmental epigenetic studies of sexual organisms confirm the capacity to respond through epigenetic variation. An epigenetic response could be even more important in a population when genetic variation is lacking. A previous study of an asexual snail, Potamopyrgus antipodarum, demonstrated that different populations derived from a single clonal lineage differed in both shell phenotype and methylation signature when comparing lake versus river populations. Here, we examine methylation variation among lakes that differ in environmental disturbance and pollution histories. Snails were collected from a more pristine rural Lake 1 (Lake Lytle), and two urban lakes, Lake 2 (Capitol Lake) and Lake 3 (Lake Washington) on the Northwest Pacific coast. DNA methylation was assessed for each sample population using methylated DNA immunoprecipitation, MeDIP, followed by next-generation sequencing. The differential DNA methylation regions (DMRs) identified among the different lake comparisons suggested a higher number of DMRs and variation between rural Lake 1 and one urban Lake 2, and between the two urban Lakes 2 and 3, but limited variation between the rural Lake 1 and urban Lake 3. DMR genomic characteristics and gene associations were investigated. The presence of site-specific differences between each of these lake populations suggest an epigenetic response to varied environmental factors. The results do not support an effect of geographic distance in these populations. The role of dispersal distance among lakes, population history, environmental pollution and stably inherited methylation versus environmentally triggered methylation in producing the observed epigenetic variation are discussed. Observations support the proposal that epigenetic alterations may associate with phenotypic variation and environmental factors and history of the different lakes.
{"title":"Regional epigenetic variation in asexual snail populations among urban and rural lakes","authors":"Jennifer L. M. Thorson, Mark W. Smithson, Ingrid Sadler‐Riggleman, Daniel Beck, M. Dybdahl, M. Skinner","doi":"10.1093/eep/dvz020","DOIUrl":"https://doi.org/10.1093/eep/dvz020","url":null,"abstract":"Abstract Epigenetic variation has the potential to influence environmentally dependent development and contribute to phenotypic responses to local environments. Environmental epigenetic studies of sexual organisms confirm the capacity to respond through epigenetic variation. An epigenetic response could be even more important in a population when genetic variation is lacking. A previous study of an asexual snail, Potamopyrgus antipodarum, demonstrated that different populations derived from a single clonal lineage differed in both shell phenotype and methylation signature when comparing lake versus river populations. Here, we examine methylation variation among lakes that differ in environmental disturbance and pollution histories. Snails were collected from a more pristine rural Lake 1 (Lake Lytle), and two urban lakes, Lake 2 (Capitol Lake) and Lake 3 (Lake Washington) on the Northwest Pacific coast. DNA methylation was assessed for each sample population using methylated DNA immunoprecipitation, MeDIP, followed by next-generation sequencing. The differential DNA methylation regions (DMRs) identified among the different lake comparisons suggested a higher number of DMRs and variation between rural Lake 1 and one urban Lake 2, and between the two urban Lakes 2 and 3, but limited variation between the rural Lake 1 and urban Lake 3. DMR genomic characteristics and gene associations were investigated. The presence of site-specific differences between each of these lake populations suggest an epigenetic response to varied environmental factors. The results do not support an effect of geographic distance in these populations. The role of dispersal distance among lakes, population history, environmental pollution and stably inherited methylation versus environmentally triggered methylation in producing the observed epigenetic variation are discussed. Observations support the proposal that epigenetic alterations may associate with phenotypic variation and environmental factors and history of the different lakes.","PeriodicalId":11774,"journal":{"name":"Environmental Epigenetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2019-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/eep/dvz020","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49282167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract The effects of in utero exposure to illicit drugs on adult offspring are a significant and widespread but understudied global health concern, particularly in light of the growing opioid epidemic and emerging therapeutic uses for cannabis, ketamine, and MDMA. Epigenetic mechanisms including DNA methylation, histone modifications, and expression of non-coding RNAs provide a mechanistic link between the prenatal environment and health consequences years beyond the original exposure, and shifts in the epigenome present in early life or adolescence can lead to disease states only appearing during adulthood. The current review summarizes the literature assessing effects of perinatal illicit drug exposure on adult disease phenotypes as mediated by perturbations of the epigenome. Both behavioral and somatic phenotypes are included and studies reporting clinical data in adult offspring, epigenetic readouts in offspring of any age, or both phenotypic and epigenetic measures are prioritized. Studies of licit substances of abuse (i.e. alcohol, nicotine) are excluded with a focus on cannabis, psychostimulants, opioids, and psychedelics; current issues in the field and areas of interest for further investigation are also discussed.
{"title":"The epigenetic legacy of illicit drugs: developmental exposures and late-life phenotypes","authors":"N. Wanner, Mathia Colwell, Christopher D. Faulk","doi":"10.1093/eep/dvz022","DOIUrl":"https://doi.org/10.1093/eep/dvz022","url":null,"abstract":"Abstract The effects of in utero exposure to illicit drugs on adult offspring are a significant and widespread but understudied global health concern, particularly in light of the growing opioid epidemic and emerging therapeutic uses for cannabis, ketamine, and MDMA. Epigenetic mechanisms including DNA methylation, histone modifications, and expression of non-coding RNAs provide a mechanistic link between the prenatal environment and health consequences years beyond the original exposure, and shifts in the epigenome present in early life or adolescence can lead to disease states only appearing during adulthood. The current review summarizes the literature assessing effects of perinatal illicit drug exposure on adult disease phenotypes as mediated by perturbations of the epigenome. Both behavioral and somatic phenotypes are included and studies reporting clinical data in adult offspring, epigenetic readouts in offspring of any age, or both phenotypic and epigenetic measures are prioritized. Studies of licit substances of abuse (i.e. alcohol, nicotine) are excluded with a focus on cannabis, psychostimulants, opioids, and psychedelics; current issues in the field and areas of interest for further investigation are also discussed.","PeriodicalId":11774,"journal":{"name":"Environmental Epigenetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2019-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/eep/dvz022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47731037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Dubois, S. Louvel, A. Le Goff, Catherine Guaspare, P. Allard
Abstract Despite the high public interest in epigenetics, few scholars have empirically investigated the forms, reasons and consequences of the public circulation of epigenetics. Using an original database focusing on ‘lifestyle’ or ‘everyday’ epigenetics, this article aims to promote an open-minded and interdisciplinary dialogue between the public appropriation of epigenetics and the current scientific state of the art. It raises three main questions: Are there any specific modes of circulation of epigenetics in the general public? Why does epigenetics seem so appealing to the public? Within the public repertoire of epigenetics, is it possible to identify some specific knowledge claims and, if so, given the current state of the art, what is their degree of accuracy? The article argues that the social diffusion of epigenetics frequently carries on beliefs and misconceptions about genetics and epigenetics. The social life of epigenetics fuels a collective ‘illusion’ of control and empowerment on the basis of which new markets expand. More unexpectedly, this article underlines the emergence of a new scientific culture, i.e. the ‘scientifization’ of the cultural appropriation of epigenetics. Our analysis can inform the scientific community about the current and evolving state of the public representation of epigenetics and help it frame outreach activities.
{"title":"Epigenetics in the public sphere: interdisciplinary perspectives","authors":"M. Dubois, S. Louvel, A. Le Goff, Catherine Guaspare, P. Allard","doi":"10.1093/eep/dvz019","DOIUrl":"https://doi.org/10.1093/eep/dvz019","url":null,"abstract":"Abstract Despite the high public interest in epigenetics, few scholars have empirically investigated the forms, reasons and consequences of the public circulation of epigenetics. Using an original database focusing on ‘lifestyle’ or ‘everyday’ epigenetics, this article aims to promote an open-minded and interdisciplinary dialogue between the public appropriation of epigenetics and the current scientific state of the art. It raises three main questions: Are there any specific modes of circulation of epigenetics in the general public? Why does epigenetics seem so appealing to the public? Within the public repertoire of epigenetics, is it possible to identify some specific knowledge claims and, if so, given the current state of the art, what is their degree of accuracy? The article argues that the social diffusion of epigenetics frequently carries on beliefs and misconceptions about genetics and epigenetics. The social life of epigenetics fuels a collective ‘illusion’ of control and empowerment on the basis of which new markets expand. More unexpectedly, this article underlines the emergence of a new scientific culture, i.e. the ‘scientifization’ of the cultural appropriation of epigenetics. Our analysis can inform the scientific community about the current and evolving state of the public representation of epigenetics and help it frame outreach activities.","PeriodicalId":11774,"journal":{"name":"Environmental Epigenetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2019-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/eep/dvz019","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46802125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-29eCollection Date: 2019-07-01DOI: 10.1093/eep/dvz014
John S House, Jonathan Hall, Sarah S Park, Antonio Planchart, Eric Money, Rachel L Maguire, Zhiqing Huang, Carolyn J Mattingly, David Skaar, Jung Ying Tzeng, Thomas H Darrah, Avner Vengosh, Susan K Murphy, Randy L Jirtle, Cathrine Hoyo
Cadmium (Cd) is a ubiquitous environmental pollutant associated with a wide range of health outcomes including cancer. However, obscure exposure sources often hinder prevention efforts. Further, although epigenetic mechanisms are suspected to link these associations, gene sequence regions targeted by Cd are unclear. Aberrant methylation of a differentially methylated region (DMR) on the MEG3 gene that regulates the expression of a cluster of genes including MEG3, DLK1, MEG8, MEG9 and DIO3 has been associated with multiple cancers. In 287 infant-mother pairs, we used a combination of linear regression and the Getis-Ord Gi* statistic to determine if maternal blood Cd concentrations were associated with offspring CpG methylation of the sequence region regulating a cluster of imprinted genes including MEG3. Correlations were used to examine potential sources and routes. We observed a significant geographic co-clustering of elevated prenatal Cd levels and MEG3 DMR hypermethylation in cord blood (P = 0.01), and these findings were substantiated in our statistical models (β = 1.70, se = 0.80, P = 0.03). These associations were strongest in those born to African American women (β = 3.52, se = 1.32, P = 0.01) compared with those born to White women (β = 1.24, se = 2.11, P = 0.56) or Hispanic women (β = 1.18, se = 1.24, P = 0.34). Consistent with Cd bioaccumulation during the life course, blood Cd levels increased with age (β = 0.015 µg/dl/year, P = 0.003), and Cd concentrations were significantly correlated between blood and urine (ρ > 0.47, P < 0.01), but not hand wipe, soil or house dust concentrations (P > 0.05). Together, these data support that prenatal Cd exposure is associated with aberrant methylation of the imprint regulatory element for the MEG3 gene cluster at birth. However, neither house-dust nor water are likely exposure sources, and ingestion via contaminated hands is also unlikely to be a significant exposure route in this population. Larger studies are required to identify routes and sources of exposure.
{"title":"Cadmium exposure and <i>MEG3</i> methylation differences between Whites and African Americans in the NEST Cohort.","authors":"John S House, Jonathan Hall, Sarah S Park, Antonio Planchart, Eric Money, Rachel L Maguire, Zhiqing Huang, Carolyn J Mattingly, David Skaar, Jung Ying Tzeng, Thomas H Darrah, Avner Vengosh, Susan K Murphy, Randy L Jirtle, Cathrine Hoyo","doi":"10.1093/eep/dvz014","DOIUrl":"https://doi.org/10.1093/eep/dvz014","url":null,"abstract":"<p><p>Cadmium (Cd) is a ubiquitous environmental pollutant associated with a wide range of health outcomes including cancer. However, obscure exposure sources often hinder prevention efforts. Further, although epigenetic mechanisms are suspected to link these associations, gene sequence regions targeted by Cd are unclear. Aberrant methylation of a differentially methylated region (DMR) on the <i>MEG3</i> gene that regulates the expression of a cluster of genes including <i>MEG3, DLK1, MEG8, MEG9</i> and <i>DIO3</i> has been associated with multiple cancers. In 287 infant-mother pairs, we used a combination of linear regression and the Getis-Ord Gi* statistic to determine if maternal blood Cd concentrations were associated with offspring CpG methylation of the sequence region regulating a cluster of imprinted genes including <i>MEG3</i>. Correlations were used to examine potential sources and routes. We observed a significant geographic co-clustering of elevated prenatal Cd levels and <i>MEG3</i> DMR hypermethylation in cord blood (<i>P</i> = 0.01), and these findings were substantiated in our statistical models (β = 1.70, se = 0.80, <i>P</i> = 0.03). These associations were strongest in those born to African American women (β = 3.52, se = 1.32, <i>P</i> = 0.01) compared with those born to White women (β = 1.24, se = 2.11, <i>P</i> = 0.56) or Hispanic women (β = 1.18, se = 1.24, <i>P</i> = 0.34). Consistent with Cd bioaccumulation during the life course, blood Cd levels increased with age (β = 0.015 µg/dl/year, <i>P</i> = 0.003), and Cd concentrations were significantly correlated between blood and urine (ρ > 0.47, <i>P</i> < 0.01), but not hand wipe, soil or house dust concentrations (<i>P</i> > 0.05). Together, these data support that prenatal Cd exposure is associated with aberrant methylation of the imprint regulatory element for the <i>MEG3</i> gene cluster at birth. However, neither house-dust nor water are likely exposure sources, and ingestion via contaminated hands is also unlikely to be a significant exposure route in this population. Larger studies are required to identify routes and sources of exposure.</p>","PeriodicalId":11774,"journal":{"name":"Environmental Epigenetics","volume":"5 3","pages":"dvz014"},"PeriodicalIF":3.8,"publicationDate":"2019-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/eep/dvz014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41195480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-29eCollection Date: 2019-07-01DOI: 10.1093/eep/dvz013
Ingrid Sadler-Riggleman, Rachel Klukovich, Eric Nilsson, Daniel Beck, Yeming Xie, Wei Yan, Michael K Skinner
Male reproductive health has been in decline for decades with dropping sperm counts and increasing infertility, which has created a significant societal and economic burden. Between the 1970s and now, a general decline of over 50% in sperm concentration has been observed in the population. Environmental toxicant-induced epigenetic transgenerational inheritance has been shown to affect testis pathology and sperm count. Sertoli cells have an essential role in spermatogenesis by providing physical and nutritional support for developing germ cells. The current study was designed to further investigate the transgenerational epigenetic changes in the rat Sertoli cell epigenome and transcriptome that are associated with the onset of testis disease. Gestating female F0 generation rats were transiently exposed during the period of fetal gonadal sex determination to the environmental toxicants, such as dichlorodiphenyltrichloroethane (DDT) or vinclozolin. The F1 generation offspring were bred (i.e. intercross within the lineage) to produce the F2 generation grand-offspring that were then bred to produce the transgenerational F3 generation (i.e. great-grand-offspring) with no sibling or cousin breeding used. The focus of the current study was to investigate the transgenerational testis disease etiology, so F3 generation rats were utilized. The DNA and RNA were obtained from purified Sertoli cells isolated from postnatal 20-day-old male testis of F3 generation rats. Transgenerational alterations in DNA methylation, noncoding RNA, and gene expression were observed in the Sertoli cells from vinclozolin and DDT lineages when compared to the control (vehicle exposed) lineage. Genes associated with abnormal Sertoli cell function and testis pathology were identified, and the transgenerational impacts of vinclozolin and DDT were determined. Alterations in critical gene pathways, such as the pyruvate metabolism pathway, were identified. Observations suggest that ancestral exposures to environmental toxicants promote the epigenetic transgenerational inheritance of Sertoli cell epigenetic and transcriptome alterations that associate with testis abnormalities. These epigenetic alterations appear to be critical factors in the developmental and generational origins of testis pathologies and male infertility.
{"title":"Epigenetic transgenerational inheritance of testis pathology and Sertoli cell epimutations: generational origins of male infertility.","authors":"Ingrid Sadler-Riggleman, Rachel Klukovich, Eric Nilsson, Daniel Beck, Yeming Xie, Wei Yan, Michael K Skinner","doi":"10.1093/eep/dvz013","DOIUrl":"10.1093/eep/dvz013","url":null,"abstract":"<p><p>Male reproductive health has been in decline for decades with dropping sperm counts and increasing infertility, which has created a significant societal and economic burden. Between the 1970s and now, a general decline of over 50% in sperm concentration has been observed in the population. Environmental toxicant-induced epigenetic transgenerational inheritance has been shown to affect testis pathology and sperm count. Sertoli cells have an essential role in spermatogenesis by providing physical and nutritional support for developing germ cells. The current study was designed to further investigate the transgenerational epigenetic changes in the rat Sertoli cell epigenome and transcriptome that are associated with the onset of testis disease. Gestating female F0 generation rats were transiently exposed during the period of fetal gonadal sex determination to the environmental toxicants, such as dichlorodiphenyltrichloroethane (DDT) or vinclozolin. The F1 generation offspring were bred (i.e. intercross within the lineage) to produce the F2 generation grand-offspring that were then bred to produce the transgenerational F3 generation (i.e. great-grand-offspring) with no sibling or cousin breeding used. The focus of the current study was to investigate the transgenerational testis disease etiology, so F3 generation rats were utilized. The DNA and RNA were obtained from purified Sertoli cells isolated from postnatal 20-day-old male testis of F3 generation rats. Transgenerational alterations in DNA methylation, noncoding RNA, and gene expression were observed in the Sertoli cells from vinclozolin and DDT lineages when compared to the control (vehicle exposed) lineage. Genes associated with abnormal Sertoli cell function and testis pathology were identified, and the transgenerational impacts of vinclozolin and DDT were determined. Alterations in critical gene pathways, such as the pyruvate metabolism pathway, were identified. Observations suggest that ancestral exposures to environmental toxicants promote the epigenetic transgenerational inheritance of Sertoli cell epigenetic and transcriptome alterations that associate with testis abnormalities. These epigenetic alterations appear to be critical factors in the developmental and generational origins of testis pathologies and male infertility.</p>","PeriodicalId":11774,"journal":{"name":"Environmental Epigenetics","volume":"5 3","pages":"dvz013"},"PeriodicalIF":4.8,"publicationDate":"2019-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/22/ec/dvz013.PMC6736068.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41195481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mammalian embryos initially develop progenitor tissues for both male and female reproductive tract organs, known as the Wolffian ducts and the Müllerian ducts, respectively. Ultimately, each individual develops a single set of male or female reproductive tract organs. Therefore, an essential step for sex differentiation is the regression of one duct and growth and differentiation of the other duct. In males, this requires Müllerian duct regression and Wolffian duct growth and differentiation. Müllerian duct regression is induced by the expression of Amh, encoding anti-Müllerian hormone, from the fetal testes. Subsequently, receptor-mediated signal transduction in mesenchymal cells surrounding the Müllerian duct epithelium leads to duct elimination. The genes that induce Amh transcription and the downstream signaling that results from Amh activity form a pathway. However, the molecular details of this pathway are currently unknown. A set of essential genes for AMH pathway function has been identified. More recently, transcriptome analysis of male and female Müllerian duct mesenchyme at an initial stage of regression has identified new genes that may mediate elimination of the Müllerian system. The evidence taken together can be used to generate an initial gene regulatory network describing the Amh pathway for Müllerian duct regression. An Amh gene regulatory network will be a useful tool to study Müllerian duct regression, sex differentiation, and its relationship to environmental influences.
{"title":"A gene regulatory network for Müllerian duct regression.","authors":"Malcolm M Moses, Richard R Behringer","doi":"10.1093/eep/dvz017","DOIUrl":"https://doi.org/10.1093/eep/dvz017","url":null,"abstract":"<p><p>Mammalian embryos initially develop progenitor tissues for both male and female reproductive tract organs, known as the Wolffian ducts and the Müllerian ducts, respectively. Ultimately, each individual develops a single set of male or female reproductive tract organs. Therefore, an essential step for sex differentiation is the regression of one duct and growth and differentiation of the other duct. In males, this requires Müllerian duct regression and Wolffian duct growth and differentiation. Müllerian duct regression is induced by the expression of <i>Amh</i>, encoding anti-Müllerian hormone, from the fetal testes. Subsequently, receptor-mediated signal transduction in mesenchymal cells surrounding the Müllerian duct epithelium leads to duct elimination. The genes that induce <i>Amh</i> transcription and the downstream signaling that results from <i>Amh</i> activity form a pathway. However, the molecular details of this pathway are currently unknown. A set of essential genes for AMH pathway function has been identified. More recently, transcriptome analysis of male and female Müllerian duct mesenchyme at an initial stage of regression has identified new genes that may mediate elimination of the Müllerian system. The evidence taken together can be used to generate an initial gene regulatory network describing the <i>Amh</i> pathway for Müllerian duct regression. An <i>Amh</i> gene regulatory network will be a useful tool to study Müllerian duct regression, sex differentiation, and its relationship to environmental influences.</p>","PeriodicalId":11774,"journal":{"name":"Environmental Epigenetics","volume":"5 3","pages":"dvz017"},"PeriodicalIF":3.8,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/eep/dvz017","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9730852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
R. Bhandari, Julia A. Taylor, Jennifer Sommerfeld-Sager, D. Tillitt, W. Ricke, F. V. vom Saal
Abstract Fetal/neonatal environmental estrogen exposures alter developmental programing of the prostate gland causing onset of diseases later in life. We have previously shown in vitro that exposures to 17β-estradiol (E2) and the endocrine disrupting chemical bisphenol A, at concentrations relevant to human exposure, cause an elevation of estrogen receptor α (Esr1) mRNA in primary cultures of fetal mouse prostate mesenchymal cells; a similar result was observed in the fetal rat urogenital sinus. Effects of these chemicals on prostate mesenchyme in vivo are not well understood. Here we show effects in mice of fetal exposure to the estrogenic drug in mixed oral contraceptives, 17α-ethinylestradiol (EE2), at a concentration of EE2 encountered by human embryos/fetuses whose mothers become pregnant while on EE2-containing oral contraceptives, or bisphenol A at a concentration relevant to exposures observed in human fetuses in vivo. Expression of Esr1 was elevated by bisphenol A or EE2 exposures, which decreased the global expression of DNA methyltransferase 3A (Dnmt3a), while methylation of Esr1 promoter was significantly increased. These results show that exposures to the environmental estrogen bisphenol A and drug EE2 cause transcriptional and epigenetic alterations to expression of estrogen receptors in developing prostate mesenchyme in vivo.
{"title":"Estrogen receptor 1 expression and methylation of Esr1 promoter in mouse fetal prostate mesenchymal cells induced by gestational exposure to bisphenol A or ethinylestradiol","authors":"R. Bhandari, Julia A. Taylor, Jennifer Sommerfeld-Sager, D. Tillitt, W. Ricke, F. V. vom Saal","doi":"10.1093/eep/dvz012","DOIUrl":"https://doi.org/10.1093/eep/dvz012","url":null,"abstract":"Abstract Fetal/neonatal environmental estrogen exposures alter developmental programing of the prostate gland causing onset of diseases later in life. We have previously shown in vitro that exposures to 17β-estradiol (E2) and the endocrine disrupting chemical bisphenol A, at concentrations relevant to human exposure, cause an elevation of estrogen receptor α (Esr1) mRNA in primary cultures of fetal mouse prostate mesenchymal cells; a similar result was observed in the fetal rat urogenital sinus. Effects of these chemicals on prostate mesenchyme in vivo are not well understood. Here we show effects in mice of fetal exposure to the estrogenic drug in mixed oral contraceptives, 17α-ethinylestradiol (EE2), at a concentration of EE2 encountered by human embryos/fetuses whose mothers become pregnant while on EE2-containing oral contraceptives, or bisphenol A at a concentration relevant to exposures observed in human fetuses in vivo. Expression of Esr1 was elevated by bisphenol A or EE2 exposures, which decreased the global expression of DNA methyltransferase 3A (Dnmt3a), while methylation of Esr1 promoter was significantly increased. These results show that exposures to the environmental estrogen bisphenol A and drug EE2 cause transcriptional and epigenetic alterations to expression of estrogen receptors in developing prostate mesenchyme in vivo.","PeriodicalId":11774,"journal":{"name":"Environmental Epigenetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/eep/dvz012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49428611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L. Lindeman, J. Thaulow, You Song, J. Kamstra, Li Xie, J. Asselman, P. Aleström, K. Tollefsen
Abstract The water flea Daphnia magna is a keystone species in freshwater ecosystems and has been widely used as a model organism in environmental ecotoxicology. This aquatic crustacean is sensitive to environmental stressors and displays considerable plasticity in adapting to changing environmental conditions. Part of this plasticity may be due to epigenetic regulation of gene expression, including changes to DNA methylation and histone modifications. Because of the generally hypomethylated genome of this species, we hypothesized that the histone code may have an essential role in the epigenetic control and that histone modifications might be an early marker for stress. This study aims to characterize the epigenetic, transcriptional and phenotypic responses and their causal linkages in directly exposed adult (F0) Daphnia and peritoneal exposed neonates (F1) after a chronic (7-day) exposure to a sublethal concentration (10 mg/l) of 5-azacytidine, a well-studied vertebrate DNA methylation inhibitor. Exposure of the F0 generation significantly reduced the cumulative fecundity, accompanied with differential expression of genes in the one-carbon-cycle metabolic pathway. In the epigenome of the F0 generation, a decrease in global DNA methylation, but no significant changes on H3K4me3 or H3K27me3, were observed. In the F1 offspring generation, changes in gene expression, a significant reduction in global DNA methylation and changes in histone modifications were identified. The results indicate that exposure during adulthood may result in more pronounced effects on early development in the offspring generation, though interpretation of the data should be carefully done since both the exposure regime and developmental period is different in the two generations examined. The obtained results improve our understanding of crustacean epigenetics and the tools developed may promote use of epigenetic markers in hazard assessment of environmental stressors.
{"title":"Epigenetic, transcriptional and phenotypic responses in two generations of Daphnia magna exposed to the DNA methylation inhibitor 5-azacytidine","authors":"L. Lindeman, J. Thaulow, You Song, J. Kamstra, Li Xie, J. Asselman, P. Aleström, K. Tollefsen","doi":"10.1093/eep/dvz016","DOIUrl":"https://doi.org/10.1093/eep/dvz016","url":null,"abstract":"Abstract The water flea Daphnia magna is a keystone species in freshwater ecosystems and has been widely used as a model organism in environmental ecotoxicology. This aquatic crustacean is sensitive to environmental stressors and displays considerable plasticity in adapting to changing environmental conditions. Part of this plasticity may be due to epigenetic regulation of gene expression, including changes to DNA methylation and histone modifications. Because of the generally hypomethylated genome of this species, we hypothesized that the histone code may have an essential role in the epigenetic control and that histone modifications might be an early marker for stress. This study aims to characterize the epigenetic, transcriptional and phenotypic responses and their causal linkages in directly exposed adult (F0) Daphnia and peritoneal exposed neonates (F1) after a chronic (7-day) exposure to a sublethal concentration (10 mg/l) of 5-azacytidine, a well-studied vertebrate DNA methylation inhibitor. Exposure of the F0 generation significantly reduced the cumulative fecundity, accompanied with differential expression of genes in the one-carbon-cycle metabolic pathway. In the epigenome of the F0 generation, a decrease in global DNA methylation, but no significant changes on H3K4me3 or H3K27me3, were observed. In the F1 offspring generation, changes in gene expression, a significant reduction in global DNA methylation and changes in histone modifications were identified. The results indicate that exposure during adulthood may result in more pronounced effects on early development in the offspring generation, though interpretation of the data should be carefully done since both the exposure regime and developmental period is different in the two generations examined. The obtained results improve our understanding of crustacean epigenetics and the tools developed may promote use of epigenetic markers in hazard assessment of environmental stressors.","PeriodicalId":11774,"journal":{"name":"Environmental Epigenetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/eep/dvz016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49058588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}