Humanized mouse models for arsenic toxicology

砷毒理学的人源化小鼠模型

基本信息

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
项目类别：
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

项目摘要

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.

项目概要饮用水和食品受到无机砷 (iAs) 污染是一个主要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、呼吸系统和神经系统疾病。人类和大多数其他哺乳动物物种已经开发出 iAs 解毒机制，其中涉及 iAs 向甲基 As (MAs) 和二甲基 As (DMAs) 的两步转化以及甲基化的排泄尿液中的代谢物。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（AS3MT）。 iAs 甲基化能力受损，例如由于 AS3MT 多态性，与 iAs 暴露相关疾病的风险增加有关。实验室已广泛研究了 iAs 暴露不利影响的机制模型。然而，实验室研究因实验动物之间的巨大差异而受到阻碍以及人类代谢 iAs 的能力。特别是，实验室小鼠已被证明可以甲基化并且解毒效率比人类高得多，因此很难在小鼠中重现一些不利的情况人口研究中报告的表型，特别是癌症和糖尿病。拟议的最终目标研究的目的是开发新型小鼠模型，其中 iAs 代谢与人类相似，并且其中可以在环境相关的 iAs 暴露水平下研究 iAs 相关疾病。我们最近生成了一种新的小鼠品系，其中 Borcs7/As3mt 基因座通过同线性进行人源化替代品。人源化 (Hs/Hs) 小鼠组织中的 AS3MT 表达与人类组织中的表达相似与小鼠 As3mt 的表达不同：AS3MT 的表达在肝脏中较低，而在肾上腺中较高。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相关。 iAs 解毒以及组织和排泄物中 iAs 及其甲基化代谢物的概况与人类报道一致。该项目的目标是：(1) 表征 Hs/Hs 小鼠对 iAs 暴露不利影响的易感性，专注于糖尿病的影响，(2) 产生表达 AS3MT 单倍型的新小鼠品系，该品系具有与人类群体中 iAs 甲基化受损和 iAs 诱发疾病的风险有关，以及 (3) 探索肾上腺 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。这些模型将使得研究 iAs 在环境相关暴露水平下的不利影响成为可能 iAs 和 AS3MT 多态性的类人代谢。使用这些模型将会显着提高重点关注 iAs 诱发疾病的实验室研究的可转化性和影响。