Chromatin contacts are germline-transmissable vehicles underlying epigenetic transgenerational inheritance

染色质接触是表观遗传跨代遗传的种系可传递载体

• 批准号: 10745221
• 负责人: BRUCE BLUMBERG
• 金额: $ 66.05万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10745221
• 关键词: Adipocytes; Adult; Affect; Animal Model; Animals; Automobile Driving; Biological; Biology; Cell Count; Cell Separation; ChIP-seq; Chemical Exposure; Chemicals; Chromatin; Chromatin Structure Alteration; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Consumption; DNA; DNA Sequence Alteration; DNA-Binding Proteins; Data; Desire for food; Diet; Dietary Fats; Disease; Dose; Embryo; Endocrine Disruptors; Environment; Environmental Exposure; Environmental Risk Factor; Enzymes; Epigenetic Process; Etiology; Experimental Designs; Experimental Models; Exposure to; Fasting; Fat-Restricted Diet; Fatty acid glycerol esters; Future; Future Generations; Gene Expression; Generations; Goals; Health; Health Care Costs; Hi-C; Higher Order Chromatin Structure; Human; Hyperglycemia; Hyperinsulinism; Inherited; Insulin Resistance; Insulinase; Intervention; Knockout Mice; Lactation; Life; Link; Literature; Liver; Memory; Messenger RNA; Metabolic Diseases; Metabolism; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Proteins; Nuclear Receptors; Obesity; Onset of illness; Outcome; Phenocopy; Phenotype; Play; Predisposition; Pregnancy; Prevention; Productivity; Public Health; Publishing; Repression; Reproducibility; Research; Resistance; Risk Assessment; Rodent; Role; Satiation; Series; Structure of primordial sex cell; Techniques; Technology; Testing; adult obesity; bisphenol A; design; disease transmission; drinking water; energy balance; environmental stressor; epigenomics; experimental study; genome analysis; hormone regulation; human model; insight; mRNA Expression; male; men' s group; metabolic phenotype; mouse model; obesity prevention; obesogen; pandemic disease; phthalates; pregnant; prenatal; prevent; rapid weight gain; response; transgenerational epigenetic inheritance; transmission process; tributyltin

Studies in animal models linked gestational exposures to endocrine disrupting chemicals (EDCs) with the onset of disease in exposed and unexposed descendants. Many groups found such transgenerational effects of chemical exposures, which were proposed to be examples of epigenetic inheritance. Transgenerational effects of environmental exposures have substantial support in the literature. Yet the concept that responses to environmental exposures can be transmitted to subsequent generations through the germline without DNA mutations remains controversial because the underlying mechanisms have not been explained satisfactorily. Understanding how effects of environmental exposures are transmitted to unexposed generations without DNA mutations is a fundamental, unanswered question in biology. We developed a highly reproducible animal model for transgenerational inheritance of obesity. When pregnant F0 mouse dams were treated with environmentally-relevant (nM) doses of TBT via their drinking water throughout gestation, increased fat accumulation was detected in F1-F4 generation male descendants. Affected TBT-group males developed a transgenerational “thrifty phenotype”: they were resistant to fat loss during fasting, rapidly gained weight when dietary fat was increased and retained this fat even after being returned to a normal, low-fat diet. Our published and preliminary results led us to propose a new model for transgenerational inheritance - that prenatal TBT exposure altered higher-order chromatin structure (HOCS), changing secondary epigenetic modifiers that inhibited expression of insulin degrading enzyme (Ide) causing diet-induced hyperinsulinemia and obesity. Here we propose a comprehensive series of experiments designed to determine exactly how exposure of pregnant F0 dams to TBT alters HOCS in F1-F3 primordial germ cells (PGCs), why these changes are inherited, rather than reversed to the normal state, how these changes affect lower-level epigenetic regulators controlling expression of Ide and why does the phenotype only occur in males. Aim 1 will identify mechanisms that drive changes HOCS near the Ide gene and how these interact with lower-level epigenetic regulators to modulate Ide expression in the adult liver. Aim 2 tests whether epigenetic interventions, such as dissolving the HOCS alterations or releasing Ide expression from repression in PGCs or adults can prevent or reverse the transgenerational predisposition to male-specific metabolic phenotypes. Deciphering the underlying mechanisms will have profound implications for how the field views transgenerational inheritance and how future experiments are planned and conducted. This new understanding will be critical to explaining the etiology of non-communicable diseases such as obesity and type 2 diabetes, targeting their causes and ameliorating their effects. Our results will have broad implications for understanding epigenetic transmission of the effects of environmental stressors and could offer opportunities to incorporate considering prevention of transgenerational inheritance into risk assessment paradigms.

在动物模型中进行的研究将妊娠期暴露于内分泌干扰化学品（EDCs）与 在暴露和未暴露的后代中发病。许多团体发现这种跨代效应 化学暴露，这被认为是表观遗传的例子。跨代 环境暴露的影响在文献中得到了大量支持。然而，这一概念的反应， 环境暴露可以通过没有DNA的生殖系传递给后代 突变仍然是有争议的，因为根本的机制还没有得到令人满意的解释。 了解环境暴露的影响如何传递给没有DNA的未暴露世代 突变是生物学中一个基本的，未解的问题。我们培育了一种繁殖能力很强的动物 肥胖的跨代遗传模型。当妊娠F0小鼠母鼠接受 在整个妊娠期间通过饮用水摄入环境相关剂量（nM）的三丁基锡化合物， 在F1-F4代雄性后代中检测到积累。受影响的TBT组男性出现了一种 跨代的“节俭表型”：他们在禁食期间抵抗脂肪减少， 膳食脂肪增加，即使恢复正常的低脂饮食后，这些脂肪也会保留下来。我们的出版 初步的研究结果使我们提出了一个新的跨代遗传模型--产前TBT 暴露改变了高阶染色质结构（HOCS），改变了二级表观遗传修饰因子， 抑制胰岛素降解酶（Ide）的表达，导致饮食诱导的高胰岛素血症和肥胖。 在这里，我们提出了一个全面的一系列实验，旨在确定如何暴露的 妊娠F0代母鼠TBT改变了F1-F3代原始生殖细胞（PGCs）中的HOCS，为什么这些变化 遗传，而不是逆转到正常状态，这些变化如何影响较低水平的表观遗传调节因子 控制Ide的表达，以及为什么这种表型只发生在男性中。目标1将确定机制 驱动改变Ide基因附近的HOCS，以及这些HOCS如何与较低水平的表观遗传调节因子相互作用， 调节成人肝脏中的Ide表达。目的2测试是否表观遗传干预，如溶解 在PGCs或成体中HOCS改变或释放Ide表达的抑制可以防止或逆转PGCs或成体中HOCS的表达。 跨代倾向于男性特定的代谢表型。解读潜在的 机制将对该领域如何看待跨代继承以及如何 未来的实验正在计划和进行中。这种新的理解对于解释 肥胖症和2型糖尿病等非传染性疾病的病因，针对其病因， 改善其效果。我们的研究结果将对理解表观遗传传递具有广泛的意义。 环境压力因素的影响，并可提供机会， 跨代遗传纳入风险评估范式。

项目成果

The unexpected teratogenicity of RXR antagonist UVI3003 via activation of PPARγ in Xenopus tropicalis.

• DOI: 10.1016/j.taap.2016.11.014
• 发表时间: 2017-01-01
• 期刊: TOXICOLOGY AND APPLIED PHARMACOLOGY
• 影响因子: 3.8
• 作者: Zhu, Jingmin;Janesick, Amanda;Wu, Lijiao;Hu, Lingling;Tang, Weiyi;Blumberg, Bruce;Shi, Huahong
• 通讯作者: Shi, Huahong

Parma consensus statement on metabolic disruptors.

• DOI: 10.1186/s12940-015-0042-7
• 发表时间: 2015-06-20
• 期刊: Environmental health : a global access science source
• 作者: Heindel JJ;Vom Saal FS;Blumberg B;Bovolin P;Calamandrei G;Ceresini G;Cohn BA;Fabbri E;Gioiosa L;Kassotis C;Legler J;La Merrill M;Rizzir L;Machtinger R;Mantovani A;Mendez MA;Montanini L;Molteni L;Nagel SC;Parmigiani S;Panzica G;Paterlini S;Pomatto V;Ruzzin J;Sartor G;Schug TT;Street ME;Suvorov A;Volpi R;Zoeller RT;Palanza P
• 通讯作者: Palanza P

Obesogens: How They Are Identified and Molecular Mechanisms Underlying Their Action.

• DOI: 10.3389/fendo.2021.780888
• 发表时间: 2021
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2
• 作者: Mohajer N;Du CY;Checkcinco C;Blumberg B
• 通讯作者: Blumberg B

Uppsala Consensus Statement on Environmental Contaminants and the Global Obesity Epidemic.

• DOI: 10.1289/ehp.1511115
• 发表时间: 2016-05-01
• 期刊: Environmental health perspectives
• 影响因子: 10.4
• 作者: Lind L;Lind PM;Lejonklou MH;Dunder L;Bergman Å;Guerrero-Bosagna C;Lampa E;Lee HK;Legler J;Nadal A;Pak YK;Phipps RP;Vandenberg LN;Zalko D;Ågerstrand M;Öberg M;Blumberg B;Heindel JJ;Birnbaum LS
• 通讯作者: Birnbaum LS

Transgenerational metabolomic fingerprints in mice ancestrally exposed to the obesogen TBT.

• DOI: 10.1016/j.envint.2021.106822
• 发表时间: 2021-12
• 期刊: Environment international
• 影响因子: 11.8
• 作者: Chamorro-García R;Poupin N;Tremblay-Franco M;Canlet C;Egusquiza R;Gautier R;Jouanin I;Shoucri BM;Blumberg B;Zalko D
• 通讯作者: Zalko D