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Epigenome-wide association of father's smoking with offspring DNA methylation: a hypothesis-generating study. 父亲吸烟与后代DNA甲基化的全表观基因组关联:一项假设生成研究。
IF 3.8 Q1 GENETICS & HEREDITY Pub Date : 2019-12-06 eCollection Date: 2019-10-01 DOI: 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.

流行病学研究表明,父亲吸烟可能会影响他们未来孩子的健康,但很少有研究表明,父系效应是否可能与后代DNA甲基化模式的改变有关。利用全表观基因组关联研究,研究父亲吸烟暴露与后代DNA甲基化之间的潜在关联。我们使用了195名男性和女性(11-54岁)的数据,参与了两个基于人群的队列。使用Illumina Infinium MethylationEPIC珠片定量全血DNA甲基化。使用Comb-p分析差异甲基化区(DMRs)。稳健的多元线性模型,调整了个人/母亲吸烟和细胞类型比例,用于分析与父亲吸烟相关的后代差异相关探针(dmp)。在敏感性分析中,我们调整了社会经济地位和家庭聚类。对通货膨胀的调整是基于BACON中经验零分布的估计。利用mismethyl的gometh功能对胞嘧啶-磷酸-鸟嘌呤(CpG)位点的注释基因进行富集和通路分析。我们发现了6个与父亲吸烟相关的显著dmr (sidak校正P值:0.0006-0.0173),这些dmr与先天免疫和适应性免疫、脂肪酸合成、神经系统和细胞过程的发育和功能有关。DMP分析鉴定出33个CpGs[错误发现率(FDR)]
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引用次数: 24
Mothers' and fathers' cognitive and affective responses to epigenetics concepts. 母亲和父亲对表观遗传学概念的认知和情感反应。
IF 3.8 Q1 GENETICS & HEREDITY Pub Date : 2019-11-25 eCollection Date: 2019-10-01 DOI: 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 (χ 2 =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。
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引用次数: 2
Regional epigenetic variation in asexual snail populations among urban and rural lakes 城乡湖泊中无性蜗牛种群的区域表观遗传变异
IF 3.8 Q1 GENETICS & HEREDITY Pub Date : 2019-10-01 DOI: 10.1093/eep/dvz020
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.
摘要表观遗传变异有可能影响环境依赖性发育,并有助于对当地环境的表型反应。性生物的环境表观遗传学研究证实了通过表观遗传学变异做出反应的能力。在缺乏遗传变异的群体中,表观遗传学反应可能更为重要。先前对无性蜗牛Potamopyrgus antipodarum的研究表明,在比较湖泊种群和河流种群时,来自单一克隆谱系的不同种群在外壳表型和甲基化特征方面存在差异。在这里,我们研究了不同环境干扰和污染历史的湖泊之间的甲基化变化。蜗牛是从西北太平洋海岸一个更原始的乡村湖泊1(莱尔湖)和两个城市湖泊2(国会湖)和3(华盛顿湖)采集的。使用甲基化DNA免疫沉淀MeDIP,然后进行下一代测序,对每个样本群体的DNA甲基化进行评估。不同湖泊比较中鉴定的差异DNA甲基化区域(DMRs)表明,农村湖泊1和一个城市湖泊2之间以及两个城市湖泊2中和3之间的DMRs数量和变异较高,但农村湖泊1与城市湖泊3之间的变异有限。研究DMR的基因组特征和基因关联。这些湖泊种群中每一个种群之间存在特定地点的差异,这表明它们对各种环境因素有表观遗传学反应。研究结果并不支持地理距离对这些人群的影响。讨论了湖泊之间的扩散距离、种群历史、环境污染和稳定遗传的甲基化与环境触发的甲基化在产生观察到的表观遗传变异中的作用。观察结果支持表观遗传学改变可能与表型变异、环境因素和不同湖泊的历史有关的观点。
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引用次数: 13
The epigenetic legacy of illicit drugs: developmental exposures and late-life phenotypes 非法药物的表观遗传遗产:发育暴露和晚年表型
IF 3.8 Q1 GENETICS & HEREDITY Pub Date : 2019-10-01 DOI: 10.1093/eep/dvz022
N. Wanner, Mathia Colwell, Christopher D. Faulk
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.
子宫内接触非法药物对成年后代的影响是一个重要而广泛但尚未得到充分研究的全球健康问题,特别是考虑到阿片类药物日益流行以及大麻、氯胺酮和MDMA的新治疗用途。表观遗传机制包括DNA甲基化、组蛋白修饰和非编码rna的表达,提供了产前环境与原始暴露数年后健康后果之间的机制联系,并且早期生活或青春期表观基因组的变化可能导致仅在成年期出现的疾病状态。本文综述了围产期非法药物暴露对表观基因组扰动介导的成人疾病表型影响的文献。包括行为表型和躯体表型,并优先考虑报告成年后代临床数据的研究,任何年龄后代的表观遗传读数,或表型和表观遗传测量。不包括对合法滥用物质(即酒精、尼古丁)的研究,重点是大麻、精神兴奋剂、类阿片和致幻剂;讨论了该领域的当前问题和值得进一步研究的领域。
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引用次数: 16
Epigenetics in the public sphere: interdisciplinary perspectives 公共领域的表观遗传学:跨学科视角
IF 3.8 Q1 GENETICS & HEREDITY Pub Date : 2019-10-01 DOI: 10.1093/eep/dvz019
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.
尽管公众对表观遗传学有很高的兴趣,但很少有学者对表观遗传学的公众传播形式、原因和后果进行实证研究。使用一个专注于“生活方式”或“日常”表观遗传学的原始数据库,本文旨在促进表观遗传学的公共拨款与当前科学技术之间的开放和跨学科对话。它提出了三个主要问题:表观遗传学在公众中是否存在任何特定的循环模式?为什么表观遗传学对公众如此有吸引力?在表观遗传学的公共曲目中,是否有可能确定一些特定的知识主张,如果是,考虑到目前的技术水平,它们的准确性是多少?文章认为,表观遗传学在社会上的传播,经常带来对遗传学和表观遗传学的信念和误解。表观遗传学的社会生活催生了一种控制和授权的集体“幻觉”,在这种幻觉的基础上,新市场得以扩张。更出人意料的是,这篇文章强调了一种新的科学文化的出现,即表观遗传学文化挪用的“科学化”。我们的分析可以告知科学界关于表观遗传学的公众代表的当前和不断发展的状态,并帮助它框架外展活动。
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引用次数: 16
Cadmium exposure and MEG3 methylation differences between Whites and African Americans in the NEST Cohort. NEST队列中白人和非裔美国人的镉暴露和MEG3甲基化差异。
IF 3.8 Q1 GENETICS & HEREDITY Pub Date : 2019-08-29 eCollection Date: 2019-07-01 DOI: 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.

镉(Cd)是一种普遍存在的环境污染物,与包括癌症在内的多种健康结果有关。然而,不明的暴露来源往往阻碍预防工作。此外,尽管表观遗传学机制被怀疑与这些关联有关,但Cd靶向的基因序列区域尚不清楚。调节包括MEG3、DLK1、MEG8、MEG9和DIO3在内的一组基因表达的MEG3基因上差异甲基化区(DMR)的异常甲基化与多种癌症有关。在287对婴儿-母亲中,我们使用线性回归和Getis-Ord-Gi*统计的组合来确定母体血液Cd浓度是否与后代调节包括MEG3在内的一组印迹基因的序列区域的CpG甲基化有关。相关性被用来检查潜在的来源和途径。我们观察到脐血中产前Cd水平升高和MEG3 DMR高甲基化的显著地理共簇性(P = 0.01),这些发现在我们的统计模型中得到了证实(β = 1.70,se = 0.80,P = 0.03)。这些关联在非裔美国女性所生的孩子中最强(β = 3.52,se = 1.32,P = 0.01)与白人女性所生的相比(β = 1.24,se = 2.11,P = 0.56)或西班牙裔女性(β = 1.18,se = 1.24,P = 0.34)。与镉在生命过程中的生物累积一致,血液中的镉水平随着年龄的增长而增加(β = 0.015 µg/dl/年,P = 0.003),并且Cd浓度在血液和尿液之间显著相关(ρ > 0.47,P P > 0.05)。总之,这些数据支持产前镉暴露与出生时MEG3基因簇的印记调节元件的异常甲基化有关。然而,室内灰尘和水都不太可能是暴露源,通过受污染的手摄入也不太可能成为该人群的重要暴露途径。需要进行更大规模的研究,以确定暴露的途径和来源。
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引用次数: 9
Epigenetic transgenerational inheritance of testis pathology and Sertoli cell epimutations: generational origins of male infertility. 睾丸病理的表观遗传学转基因遗传和支持细胞表观突变:男性不育的世代起源。
IF 4.8 Q1 GENETICS & HEREDITY Pub Date : 2019-08-29 eCollection Date: 2019-07-01 DOI: 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.

几十年来,男性生殖健康一直在下降,精子数量下降,不孕不育增加,这造成了巨大的社会和经济负担。从20世纪70年代到现在,人群中的精子浓度普遍下降了50%以上。环境毒物诱导的表观遗传已被证明会影响睾丸病理和精子数量。支持细胞通过为发育中的生殖细胞提供物理和营养支持,在精子发生中发挥着重要作用。目前的研究旨在进一步研究与睾丸疾病发作相关的大鼠支持细胞表观基因组和转录组的转基因表观遗传学变化。妊娠雌性F0代大鼠在胎儿性腺性别测定期间短暂暴露于环境毒物,如二氯二苯基三氯乙烷(DDT)或长春唑啉。对F1代后代进行繁殖(即在谱系内进行杂交)以产生F2代大后代,然后对其进行繁殖以产生转基因F3代(即大后代),而不使用兄弟姐妹或表亲繁殖。本研究的重点是研究转基因睾丸疾病的病因,因此使用F3代大鼠。DNA和RNA是从F3代大鼠出生后20天大的雄性睾丸中分离的纯化Sertoli细胞中获得的。与对照(载体暴露)谱系相比,在长春花唑啉和滴滴涕谱系的支持细胞中观察到DNA甲基化、非编码RNA和基因表达的跨代变化。鉴定了与支持细胞功能异常和睾丸病理相关的基因,并测定了长春花唑啉和滴滴涕对转基因的影响。关键基因途径的改变,如丙酮酸代谢途径,被鉴定。观察结果表明,祖先暴露于环境毒物会促进支持细胞的表观遗传和转录组改变,这些改变与睾丸异常有关。这些表观遗传学改变似乎是睾丸病理和男性不育的发育和世代起源的关键因素。
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引用次数: 0
A gene regulatory network for Müllerian duct regression. <s:1>勒氏管回归的基因调控网络。
IF 3.8 Q1 GENETICS & HEREDITY Pub Date : 2019-07-01 DOI: 10.1093/eep/dvz017
Malcolm M Moses, Richard R Behringer

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.

哺乳动物胚胎最初发育为雄性和雌性生殖道器官的祖组织,分别称为Wolffian管和mellerian管。最终,每个个体都发育出一套男性或女性生殖道器官。因此,性别分化的一个重要步骤是一个导管的回归和另一个导管的生长和分化。在男性中,这需要勒氏管退化和Wolffian管生长和分化。胎儿睾丸中编码抗勒氏管激素的Amh的表达诱导了勒氏管退化。随后,在导管上皮周围的间充质细胞中,受体介导的信号转导导致导管消除。诱导Amh转录的基因和Amh活性产生的下游信号传导形成一条通路。然而,这一途径的分子细节目前尚不清楚。已经确定了AMH通路功能的一组必需基因。最近,在退化的初始阶段,对雄性和雌性马勒氏管间质的转录组分析已经确定了可能介导马勒氏系统消除的新基因。这些证据一起可以用来产生一个初始的基因调控网络,描述Amh途径的勒氏管回归。Amh基因调控网络将为研究勒氏管回归、性别分化及其与环境影响的关系提供有用的工具。
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引用次数: 13
Estrogen receptor 1 expression and methylation of Esr1 promoter in mouse fetal prostate mesenchymal cells induced by gestational exposure to bisphenol A or ethinylestradiol 妊娠期暴露于双酚A或乙炔雌二醇诱导的小鼠胎儿前列腺间充质细胞雌激素受体1表达和Esr1启动子甲基化
IF 3.8 Q1 GENETICS & HEREDITY Pub Date : 2019-07-01 DOI: 10.1093/eep/dvz012
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.
摘要胎儿/新生儿环境雌激素暴露会改变前列腺的发育程序,导致日后疾病的发作。我们之前已经在体外表明,在胎儿小鼠前列腺间充质细胞的原代培养中,暴露于与人类暴露相关浓度的17β-雌二醇(E2)和内分泌干扰化学物质双酚A会导致雌激素受体α(Esr1)mRNA升高;在胎鼠泌尿生殖窦中也观察到类似的结果。这些化学物质对体内前列腺间充质的影响尚不清楚。在这里,我们展示了胎儿暴露于混合口服避孕药中的雌激素药物17α-乙炔雌二醇(EE2)对小鼠的影响,该药物的浓度为人类胚胎/母亲在服用含有EE2的口服避孕药时怀孕的胎儿所遇到的EE2,或与体内人类胎儿中观察到的暴露浓度相关的双酚a。双酚A或EE2暴露使Esr1的表达升高,这降低了DNA甲基转移酶3A(Dnmt3a)的整体表达,而Esr1启动子的甲基化显著增加。这些结果表明,暴露于环境雌激素双酚A和药物EE2导致体内发育中的前列腺间充质中雌激素受体表达的转录和表观遗传学改变。
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引用次数: 15
Epigenetic, transcriptional and phenotypic responses in two generations of Daphnia magna exposed to the DNA methylation inhibitor 5-azacytidine 暴露于DNA甲基化抑制剂5-氮杂胞苷的两代水蚤的表观遗传、转录和表型反应
IF 3.8 Q1 GENETICS & HEREDITY Pub Date : 2019-07-01 DOI: 10.1093/eep/dvz016
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.
摘要大型水蚤是淡水生态系统中的重要物种,在环境生态毒理学中被广泛用作模式生物。这种水生甲壳类动物对环境压力敏感,在适应不断变化的环境条件方面表现出相当大的可塑性。这种可塑性部分可能是由于基因表达的表观遗传调控,包括DNA甲基化和组蛋白修饰的变化。由于该物种的基因组普遍低甲基化,我们假设组蛋白密码可能在表观遗传学控制中发挥重要作用,组蛋白修饰可能是应激的早期标志。本研究旨在表征长期(7天)暴露于亚致死浓度(10 mg/l)5-氮杂胞苷(一种研究充分的脊椎动物DNA甲基化抑制剂)后,直接暴露于成年(F0)水蚤和腹膜暴露于新生儿(F1)的表观遗传学、转录和表型反应及其因果关系。F0代的暴露显著降低了累积繁殖力,并伴随着单碳循环代谢途径中基因的差异表达。在F0代的表观基因组中,观察到整体DNA甲基化减少,但H3K4me3或H3K27me3没有显著变化。在F1后代中,发现了基因表达的变化、整体DNA甲基化的显著减少和组蛋白修饰的变化。研究结果表明,成年期的暴露可能会对后代的早期发育产生更明显的影响,但应仔细解释数据,因为所检查的两代人的暴露状态和发育期都不同。所获得的结果提高了我们对甲壳类动物表观遗传学的理解,所开发的工具可能会促进表观遗传学标记在环境压力源危害评估中的应用。
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引用次数: 24
期刊
Environmental Epigenetics
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