Endocrine Disruptors: Assessment of endocrine disruption activity, mechanism and

内分泌干​​扰物：评估内分泌干扰活性、机制和

• 批准号: 7940433
• 负责人: Subhrangsu S Mandal
• 金额: $ 44.49万
• 依托单位: UNIVERSITY OF TEXAS ARLINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-10 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7940433
• 关键词: Adverse effects; Animals; Asses; Awareness; Behavior; Binding; Biochemical; Biochemistry; Biological Assay; Breast; Cause of Death; Cells; Chemicals; Chromatin; Communities; Community Outreach; Development; Disease; Embryonic Development; Endocrine Disruptors; Endocrine disruption; Environmental Risk Factor; Enzymes; Epigenetic Process; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Family; Food; Food Habits; Gene Activation; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genital system; Geographic Locations; Hair; Hand; Health; Histones; Homeobox Genes; Hormonal; Hormones; Human; Incidence; Knowledge; Laboratories; Learning; Life; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Pesticides; Plastics; Process; Regulation; Relative (related person); Reproduction; Response Elements; Risk; Running; Sequence Analysis; Services; Signal Transduction; Skeletal Development; Societies; Source; Syndrome; Transcriptional Regulation; Transferase; United States; base; chromatin modification; drinking water; foot; human disease; in vivo; insight; leukemia; novel; outreach; paralogous gene; promoter; public health relevance; receptor binding; research study; steroid hormone

DESCRIPTION (provided by applicant): Cancer is a major cause of death in United States and around the world. Numerous studies suggest that in addition to genetic factors, environmental factors, food habit and geographic location have significant contribution to the rate of cancer incidence. Among the environmental factors Endocrine Disrupting Chemicals (EDCs) appear to be a major contributor towards several human diseases including cancer. EDCs are family of chemicals that mimic hormones and interfere with normal hormonal functions resulting in adverse effects on human and animal health. Sources of EDCs may include daily foods, drinking water, plastics, pesticides, synthetic hormones etc. Although EDCs are major health concern, knowledge is still limited in terms of their endocrine disruption activity, mechanism of action and health risk. Based on our expertise on estrogen signaling, gene regulation and epigenetics biochemistry, we proposed to a) asses the endocrine disruption activity of various known and unknown EDCs, b) understand their mechanism of action and c) outreach to the community to increase the awareness about EDCs. In order to develop assays for the analysis of EDC activity, we propose to utilize the promoter of estrogen responsive HOX genes that are key players in embryonic development. Recently, we found that estrogen (E2) transcriptionally regulates several HOX genes including HOXC13 and paralogous genes (HOXA13, B13 and D13). HOXC13 promoter contains multiple estrogen response elements (EREs) to which estrogen receptors (ER: ERa and ER¿) bind during E2-mediated gene activation. Importantly, we also found that mixed lineage leukemia (MLL) family of histone methyl-transferases that are crucial players in gene activation, interact with ERs and bind to these EREs to regulate HOXC13 expression in presence of E2. Based on these findings, we hypothesize that HOXC13 and paralogous genes are regulated by ERs and MLLs (as coregulators). Herein, we propose to investigate the epigenetic regulatory mechanisms of E2-mediated transcriptional regulation of HOXC13 and paralogous genes and expand this knowledge to develop novel cell based assays to assess the endocrine disruption activity of various known and unknown EDCs and understand their mechanisms of action. In addition, we also propose to outreach to the community (through service learning) to increase awareness about EDCs. These studies will unfold the epigenetic regulatory mechanism of E2- mediated regulation of HOX genes. In addition, these studies will provide novel insights about the action of EDCs and also provide novel assays to assess the endocrine disruption activities of various known and unknown EDCs. The outreach activity will increase the local community awareness about EDCs and their relevance to human health and society that will have high impact on quality of human health, and may reduce the incidence of cancer and other diseases. PUBLIC HEALTH RELEVANCE: Endocrine Disrupting Chemicals (EDCs) are family of chemicals that mimic hormones and interfere with normal hormonal functions resulting in adverse effects on reproduction, behavior and development ultimately causing severe human diseases including cancer. Herein, experiments are proposed to a) asses the endocrine disruption activity of various known and unknown EDCs, b) understand their mechanism of action and c) outreach to the community to increase the awareness about EDCs. These studies will have high impact on quality of human life, health and may reduce the incidence of cancer and other diseases in long run.

描述（由申请人提供）： 癌症是美国和世界各地的主要死亡原因。大量研究表明，除了遗传因素外，环境因素、饮食习惯和地理位置对癌症发病率也有显着影响。在环境因素中，内分泌干扰化学品 (EDC) 似乎是导致包括癌症在内的多种人类疾病的主要原因。EDC 是模仿激素并干扰正常激素功能的化学物质家族，从而对人类和动物健康产生不利影响。 EDC 的来源可能包括日常食品、饮用水、塑料、杀虫剂、合成激素等。尽管 EDC 是主要的健康问题，但根据我们的专业知识，对其内分泌干扰活性、作用机制和健康风险的了解仍然有限。在雌激素信号传导、基因调控和表观遗传学生物化学方面，我们建议 a) 评估各种已知和未知 EDC 的内分泌干扰活性，b) 了解其作用机制，以及 c) 向社区进行宣传，以提高对这些问题的认识为了开发分析 EDC 活性的方法，我们建议利用雌激素反应性 HOX 基因的启动子，这些基因是胚胎发育的关键因素。最近，我们发现雌激素 (E2) 转录调节包括 HOXC13 和 HOXC13 在内的多个 HOX 基因。旁系同源基因（HOXA13、B13 和 D13）包含多个雌激素受体（ER：ERa 和 ER¿）的雌激素反应元件 (ERE)。 ）重要的是，我们还发现组蛋白甲基转移酶的混合谱系白血病（MLL）家族在基因激活中发挥着关键作用，与 ER 相互作用并与这些 ERE 结合以在存在 E2 的情况下调节 HOXC13 的表达。 E2.基于这些发现，我们发现 HOXC13 和旁系同源基因受到 ER 和 MLL（作为核心调节因子）的调节。 E2 介导的 HOXC13 和旁系同源基因转录调控的表观遗传调控机制，并扩展了这一知识，以开发新的基于细胞的测定法，以评估各种已知和未知 EDC 的内分泌干扰活性，并了解它们的作用机制。向社区宣传（通过服务学习）以提高对 EDC 的认识。这些研究将揭示 E2 介导的 HOX 基因调控的表观遗传调控机制。此外，这些研究还将提供有关 EDC 作用的新见解。并提供新的检测方法来评估各种已知和未知的内分泌干扰物活动。外展活动将提高当地社区对内分泌干扰物及其与人类健康和社会的相关性的认识，这将对人类健康质量产生重大影响，并可能会提高当地社区对内分泌干扰物的认识。减少癌症和其他疾病的发病率。 公共健康相关性：内分泌干扰化学品 (EDC) 是模仿激素并干扰正常激素功能的化学物质家族，对生殖、行为和发育产生不利影响，最终导致包括癌症在内的严重人类疾病。各种已知和未知 EDC 的内分泌干扰活性，b) 了解其作用机制，c) 向社区宣传以提高对 EDC 的认识。这些研究将对 EDC 的质量产生重大影响。人类生命、健康从长远来看可能会减少癌症和其他疾病的发病率。

项目成果

LncRNA HOTAIR: A master regulator of chromatin dynamics and cancer.

• DOI: 10.1016/j.bbcan.2015.07.001
• 发表时间: 2015-08
• 期刊: Biochimica et biophysica acta
• 作者: Bhan A;Mandal SS
• 通讯作者: Mandal SS

Long Noncoding RNA and Cancer: A New Paradigm.

• DOI: 10.1158/0008-5472.can-16-2634
• 发表时间: 2017-08-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Bhan A;Soleimani M;Mandal SS
• 通讯作者: Mandal SS

Antisense oligonucleotide mediated knockdown of HOXC13 affects cell growth and induces apoptosis in tumor cells and over expression of HOXC13 induces 3D-colony formation.

• DOI: 10.1039/c2ra22006g
• 发表时间: 2013-01-01
• 期刊: RSC advances
• 影响因子: 3.9
• 作者: Kasiri S;Ansari KI;Hussain I;Bhan A;Mandal SS
• 通讯作者: Mandal SS

Bisphenol-A induces expression of HOXC6, an estrogen-regulated homeobox-containing gene associated with breast cancer.

• DOI: 10.1016/j.bbagrm.2015.02.003
• 发表时间: 2015-06
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
• 影响因子: 4.7
• 作者: Hussain, Imran;Bhan, Arunoday;Ansari, Khairul I.;Deb, Paromita;Bobzean, Samara A. M.;Perrotti, Linda I.;Mandal, Subhrangsu S.
• 通讯作者: Mandal, Subhrangsu S.

Histone methylase MLL1 has critical roles in tumor growth and angiogenesis and its knockdown suppresses tumor growth in vivo.

• DOI: 10.1038/onc.2012.352
• 发表时间: 2013-07-11
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Ansari, K. I.;Kasiri, S.;Mandal, S. S.
• 通讯作者: Mandal, S. S.