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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.

项目总结