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.

动物模型研究表明，妊娠期接触内分泌干扰物 (EDC) 与 许多研究小组都发现了这种跨代效应。 化学暴露，这被认为是表观遗传的例子。 然而，环境暴露的影响在文献中得到了充分的支持。 环境暴露可以通过种系传播给后代，无需 DNA 突变仍然存在争议，因为其潜在机制尚未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尚未解答的基本问题。我们开发了一种高度可复制的动物。 肥胖跨代遗传模型 当怀孕的 F0 小鼠接受治疗时。 整个妊娠期间通过饮用水摄入环境相关 (nM) 剂量的 TBT，增加脂肪 在受影响的 TBT 组雄性后代中检测到积累。 跨代“节俭表型”：他们在禁食期间对减脂有抵抗力，而在禁食期间体重迅速增加 即使在恢复正常的低脂饮食后，膳食脂肪也会增加并保留这种脂肪。 初步结果使我们提出了一种新的跨代遗传模式——产前TBT 暴露改变了高阶染色质结构（HOCS），改变了次级表观遗传修饰因子 抑制胰岛素降解酶（Ide）的表达，导致饮食引起的高胰岛素血症和肥胖。 在这里，我们提出了一系列全面的实验，旨在准确确定暴露的方式 怀孕的 F0 母鼠 TBT 改变了 F1-F3 原始生殖细胞 (PGC) 的 HOCS，为什么这些变化是 这些变化如何影响较低水平的表观遗传调节因子是遗传的，而不是逆转到正常状态 控制 Ide 的表达以及为什么该表型仅发生在男性中 目标 1 将确定机制。 驱动 Ide 基因附近 HOCS 变化的因素，以及这些变化如何与较低水平的表观遗传调节因子相互作用 目标 2 调节成人肝脏中的 Ide 表达，测试是否存在表观遗传干预，例如溶解 Ide。 HOCS 改变或释放 PGC 或成人中 Ide 表达的抑制可以预防或逆转 解读男性特有的代谢表型的跨代倾向。 机制将对该领域如何看待跨代遗传以及如何看待跨代遗传产生深远的影响。 计划和进行未来的实验对于解释这一点至关重要。 肥胖和 2 型糖尿病等非传染性疾病的病因学，针对其原因和 改善它们的影响将对理解表观遗传传播产生广泛的影响。 环境压力因素的影响，并可以提供机会纳入考虑预防 将跨代遗传纳入风险评估范式。

项目成果

PFAS and Potential Adverse Effects on Bone and Adipose Tissue Through Interactions With PPARγ.

PFAS 以及通过与 PPARγ 相互作用对骨和脂肪组织的潜在不利影响。

• 发表时间: 2021
• 影响因子: 4.8
• 作者: Kirk, Andrea B;Michelsen;Rosen, Cliff;Martin, Clyde F;Blumberg, Bruce
• 通讯作者: Blumberg, Bruce

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

乌普萨拉关于环境污染物和全球肥胖流行病的共识声明。

• 发表时间: 2016-05-01
• 影响因子: 10.4
• 作者: Lind, Lars;Lind, P Monica;Lejonklou, Margareta H;Dunder, Linda;Bergman, Åke;Guerrero;Lampa, Erik;Lee, Hong Kyu;Legler, Juliette;Nadal, Angel;Pak, Youngmi Kim;Phipps, Richard P;Vandenberg, Laura N;Zalko, Daniel;Ågerstrand, Mar
• 通讯作者: Ågerstrand, Mar

Endocrine Disruptors and Health Effects in Africa: A Call for Action.

非洲的内分泌干扰物和健康影响：行动呼吁。

• 发表时间: 2017-08-22
• 影响因子: 10.4
• 作者: Bornman, Maria S;Aneck;de Jager, Christiaan;Wagenaar, Gesina M;Bouwman, Hindrik;Barnhoorn, Irene E J;Patrick, Sean M;Vandenberg, Laura N;Kortenkamp, Andreas;Blumberg, Bruce;Kimmins, Sarah;Jegou, Bernard;Auger, Jacques;DiGangi
• 通讯作者: DiGangi

Transgenerational inheritance of prenatal obesogen exposure.

产前肥胖原暴露的跨代遗传。

• 发表时间: 2014-12
• 影响因子: 4.1
• 作者: Janesick, Amanda S;Shioda, Toshihiro;Blumberg, Bruce
• 通讯作者: Blumberg, Bruce

2,4-Di-tert-butylphenol Induces Adipogenesis in Human Mesenchymal Stem Cells by Activating Retinoid X Receptors.

2,4-二叔丁基苯酚通过激活类维生素A X 受体诱导人间充质干细胞的脂肪生成。

• 发表时间: 2023-02-11
• 影响因子: 4.8
• 作者: Ren, Xiao;Chang, Richard C;Huang, Yikai;Amorim Amato, Angélica;Carivenc, Coralie;Grimaldi, Marina;Kuo, Yun;Balaguer, Patrick;Bourguet, William;Blumberg, Bruce
• 通讯作者: Blumberg, Bruce