Humanized mouse models for arsenic toxicology

砷毒理学的人源化小鼠模型

• 批准号: 10653131
• 负责人: Beverly H Koller
• 金额: $ 41.01万
• 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/10653131
• 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; Environment; 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 用无机砷（IAS）污染饮用水和食物是公共卫生的主要风险 美国和全球。接触IAS已与癌症，糖尿病，心血管，呼吸道和 神经疾病。 人类和大多数其他哺乳动物物种已开发出用于IAS排毒的机制，其中涉及 IAS到甲基AS（MAS）和二甲基-AS（DMA）的两步转换以及甲基化的排泄 尿液中的代谢产物。在哺乳动物中，IAS甲基化由单个酶的直系同源物催化 甲基转移酶（AS3MT）。甲基化IAS的能力受损，例如，由于AS3MT多态性， 与与IAS暴露相关的疾病风险增加了。 使用实验室对IAS暴露不利影响的基础机制进行了广泛研究 型号。但是，实验动物之间的实质差异阻碍了实验室研究 人类以代谢IAS的能力。特别是，实验室小鼠已显示出甲基甲酯 与人类相比，对IAS的排毒效率要高得多，因此很难在小鼠中繁殖一些不良 人群研究中报道的表型，特别是癌症和糖尿病。提议的最终目标 研究是开发新的小鼠模型，其中IAS代谢类似于人类和 可以在环境相关的IAS暴露水平上研究与IAS相关的疾病。 我们最近产生了一种新的小鼠菌株，其中borcs7/as3mt基因座是通过同时性化的 替代品。人源化（HS/HS）小鼠组织中的AS3MT表达类似于人类组织 与小鼠AS3MT：AS3MT表达的表达不同，肾上腺的表达较低。 值得注意的是，HS/HS小鼠组织中AS3MT表达的不同模式与低效率有关 IAS解毒以及IAS及其甲基化代谢产物的特征在组织和排泄物中 与人类报道的人一致。 该项目的目标是：（1）表征HS/HS小鼠对IAS暴露不利影响的敏感性， （2）专注于糖尿病生成作用，以产生一种新的小鼠菌株，表达AS3MT单倍型 与IAS甲基化受损和IAS诱导疾病的风险相关，（3）探索 肾上腺中AS3MT表达与肾上腺功能之间的关联。 拟议的研究将生成并验证独特的IAS毒理学小鼠模型。这些模型将 使研究IAS在环境相关的暴露水平以及与 IAS和AS3MT多态性的人类代谢。使用这些模型将显着改善 侧重于IAS诱发疾病的实验室研究的翻译性和影响。