Humanized mouse models for arsenic toxicology

砷毒理学的人源化小鼠模型

• 批准号: 10470377
• 负责人: Beverly H Koller
• 金额: $ 41.82万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-17 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470377
• 关键词: Adrenal Glands; Adrenal hormone preparation; Adverse effects; Affect; Animal Model; Arsenic; Beta Cell; Carcinogens; Cardiovascular Diseases; Complex; Development; Diabetes Mellitus; Disease; Drug Metabolic Detoxication; Environmental Exposure; Enzymes; Excretory function; Exposure to; Female; Food; Functional disorder; Genes; Genetic Polymorphism; Glucocorticoids; Glucose; Goals; Haplotypes; Hormones; Human; Hyperglycemia; Hypothalamic structure; Impairment; Insulin Resistance; Laboratories; Laboratory Animals; Laboratory Research; Laboratory Study; Laboratory mice; Link; Liver; Malignant Neoplasms; Mammals; Metabolism; Methylation; Methyltransferase; Modeling; Molecular; Mouse Strains; Mus; Obesity; Orthologous Gene; Pattern; Phenotype; Pituitary Gland; Population; Population Study; Predisposition; Production; Public Health; Regulator Genes; Reporting; Research; Respiratory Disease; Risk; Role; Signal Transduction; Stress Tests; Tissues; Toxicology; Urine; Wild Type Mouse; base; behavior test; biological adaptation to stress; cancer risk; cohort; contaminated drinking water; design; diabetic; diabetogenic; disorder risk; drinking water; human tissue; humanized mouse; hypothalamic-pituitary-adrenal axis; impaired capacity; improved; insulin tolerance; male; metabolic phenotype; mouse model; nervous system disorder; novel; public health relevance; toxicant

PROJECT SUMMARY Contamination of drinking water and foods with inorganic arsenic (iAs) represents a major public health risk in the U.S. and worldwide. Exposure to iAs has been linked to cancer, diabetes, cardiovascular, respiratory and neurological diseases. Humans and most other mammalian species have developed mechanism for detoxification of iAs, which involves a two-step conversion of iAs to methyl-As (MAs) and dimethyl-As (DMAs) and excretion of the methylated metabolites in urine. In mammals, iAs methylation is catalyzed by orthologs of a single enzyme, arsenic methyltransferase (AS3MT). An impaired capacity to methylate iAs, e.g., due to AS3MT polymorphism, has been linked to increased risk of diseases associated with iAs exposure. Mechanisms underlying the adverse effects of iAs exposure have been extensively studied using laboratory models. However, laboratory research has been hindered by substantial differences between laboratory animals and humans in their capacity to metabolize iAs. In particular, laboratory mice have been shown to methylate and detoxify iAs much more efficiently than humans, making it difficult to reproduce in mice some of the adverse phenotypes reported in population studies, specifically cancer and diabetes. The ultimate goal of the proposed research is to develop novel mouse models, in which iAs metabolism resembles that in humans and in which iAs-associated diseases can be studied at environmentally relevant iAs exposure levels. We have recently generated a new mouse strain in which the Borcs7/As3mt locus was humanized by syntenic replacement. AS3MT expression in tissues of the humanized (Hs/Hs) mice resembles that in human tissues and differs from expression of mouse As3mt: AS3MT expression is lower in livers and much higher in adrenals. Notably, the different pattern of AS3MT expression in tissues of Hs/Hs mice is associated with low efficiency of iAs detoxification and with the profiles for iAs and its methylated metabolites in tissues and excreta that are consistent with those reported in humans. The goals of this project are: (1) To characterize susceptibility of Hs/Hs mice to adverse effects of iAs exposure, focusing on the diabetogenic effects, (2) to generate a new mouse strain expressing AS3MT haplotype that has been linked to impaired iAs methylation and risk of iAs-induced diseases in human cohorts, and (3) to explore association between AS3MT expression in adrenals and adrenal function. The proposed research will generate and validate unique mouse models for iAs toxicology. These models will make it possible to study adverse effects of iAs at environmentally relevant exposure levels and in context with human-like metabolism of iAs and AS3MT polymorphism. Using these models will markedly improve translatability and impact of laboratory studies focusing on iAs induced diseases.

项目摘要 饮用水和食品被无机砷污染是一个重大的公共卫生风险， 美国和全世界。接触iAs与癌症、糖尿病、心血管疾病、呼吸系统疾病和 神经系统疾病 人类和大多数其他哺乳动物物种已经开发出iAs解毒机制，其中包括 iAs两步转化为甲基As（MAs）和二甲基As（DMAs）并排泄甲基化物质 尿液中的代谢物。在哺乳动物中，iAs甲基化是由单一酶砷的直系同源物催化的。 甲基转移酶（AS 3 MT）。甲基化iAs的能力受损，例如，由于AS 3 MT多态性， 与iAs暴露相关的疾病风险增加有关。 iAs暴露不良影响的潜在机制已被广泛研究，使用实验室 模型然而，实验室研究一直受到实验动物之间的实质性差异的阻碍 和人类代谢iAs的能力。特别是，实验室小鼠已被证明甲基化 并且比人类更有效地解毒iAs，使得小鼠难以复制一些不利的 人群研究中报告的表型，特别是癌症和糖尿病。建议的最终目标 研究是开发新的小鼠模型，其中iAs代谢类似于人类， 可在环境相关的iAs接触水平下研究iAs相关疾病。 我们最近已经产生了一种新的小鼠品系，其中Borcs 7/As 3 mt基因座通过同线突变被人源化。 更换.人源化（Hs/Hs）小鼠组织中的AS 3 MT表达与人组织中的相似 与小鼠As 3 mt的表达不同：AS 3 MT在肝脏中表达较低，而在肾上腺中表达较高。 值得注意的是，Hs/Hs小鼠组织中AS 3 MT表达的不同模式与低效率的免疫抑制有关。 iAs解毒和iAs及其甲基化代谢物在组织和排泄物中的分布， 与人类报告的一致。 本课题的主要目的是：（1）研究小鼠对iAs暴露的敏感性， 关注糖尿病发生效应，（2）产生表达AS 3 MT单倍型的新小鼠品系，其具有 与人类队列中iAs甲基化受损和iAs诱导疾病的风险有关，以及（3）探索 肾上腺AS 3 MT表达与肾上腺功能之间的关系。 拟议的研究将生成并验证iAs毒理学的独特小鼠模型。这些模型将 使人们有可能在与环境相关的接触水平上，并在以下情况下，研究iAs的不利影响： iAs和AS 3 MT多态性类人代谢。使用这些模型将显著改善 着重于iAs诱发疾病的实验室研究的可翻译性和影响。