Dietary phytochelatins and their impact on cadmium toxicity in the male reproductive system

膳食植物螯合素及其对男性生殖系统镉毒性的影响

基本信息

批准号：
10389418
负责人：
Zachery Ryan Jarrell
金额：
$ 6.98万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-15 至 2023-06-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10389418
关键词：
Address Air Animals Antioxidants Biology Cadmium Cell model Cells Chelating Agents Chronic Complex Couples Cysteine Cystine Data Databases Demographic Factors Diet Dietary Cadmium Dietary intake Disulfides Doctor of Philosophy Domestic Fowls Dose Drug Metabolic Detoxication Electrocardiogram Environment Environmental Exposure Environmental Risk Factor Excretory function Exposure to Fertility Food Foundations Generations Glutathione Glutathione Disulfide Goals Heavy Metals High Pressure Liquid Chromatography Histopathology Human Human body Impairment Inductively Coupled Plasma Mass Spectrometry Intervention Ions Isotope Labeling Liquid substance Lung Male Genital Organs Mammals Measures Mediator of activation protein Metabolic Metabolism Metal exposure Metals Methodology Mus Online Systems Oxidation-Reduction Oxidative Stress Peptides Peroxidases Persons Plants Population Proteins Public Health Reactive Oxygen Species Regulation Reproductive Health Research Resolution Risk Role Route Science Sperm Count Procedure Stress Sulfhydryl Compounds Supplementation System Systems Analysis Techniques Technology Testing Tissues Toxic effect Toxicology Tracer Training Urine Work antioxidant enzyme career career development data repository dietary drinking water enzyme activity epigenomics experience experimental study exposed human population human male human tissue improved interest lifestyle factors male male fertility metabolomics metal chelator metal complex mouse model multiple omics phytochelatin post-doctoral training prevent reproductive reproductive function reproductive organ reproductive tract selenoenzyme sperm cell sperm quality toxicant virtual

项目摘要

PROJECT SUMMARY Male fertility has been on the decline in recent decades, and this is due in part to the large number of environmental exposures humans encounter daily. Among these, the heavy metal, cadmium (Cd), is a notable male reproductive toxicant which is present in the air, drinking water, and numerous components of the diet, and the average person is exposed to 30 µg per day through their diet. Cd is toxic through a number of mechanisms, but much of its effects are caused through generation of oxidative stress and interference with antioxidant defenses. Plant systems deal with toxic Cd and other heavy metal exposures by producing phytochelatins (PyCs), metal chelating peptides with a high thiol content. PyCs are present in virtually any human diet, but their function in the human body is unstudied. The PyC-Cd interactions detailed in plants, along with preliminary findings of PyC in human urine, leads to the hypothesis that dietary PyCs can intervene against dietary Cd in an animal system. This will be tested by use of multiple omics technologies as well as techniques for assessing redox biology and multiple measures of male fertility and reproductive health. Aim 1 will determine the metabolism and distribution of PyCs throughout a murine model by use of high-resolution metabolomics and an isotopically labeled tracer, and the impact of PyC treatment on metal distributions will be determined by use of high-resolution metabolomics and metallomics. Aim 2 will determine the effects of PyC administration alongside Cd exposures in the male reproductive system by analyses of redox potentials and antioxidant enzyme activity as well as a multi-omics (metabolomics, metallomics, and epigenomics) analysis of reproductive tissues alongside assessments of fertility, sperm quality and histopathology. These experiments will generate critical integrative omics of dietary Cd’s impact on the redox systems which protect male reproductive health, and they will result in interventions for improving general and reproductive health in populations strongly impacted by Cd exposures by demonstrating dietary phytochelatins as metal detoxifiers in humans.

项目摘要近几十年以来，男性生育能力一直在下降，这部分归功于大量环境暴露于人类每天遇到。其中，重金属，镉（CD）是一个显着的男性生殖有毒物质存在于空中，饮用水和饮食的众多成分中，普通人每天通过饮食暴露于30 µg。 CD通过多种机制有毒，但是它的大部分作用是由于产生氧化应激和抗氧化剂的干扰而引起的防御。植物系统通过产生植物切切素处理有毒CD和其他重金属暴露（PYC），具有高硫醇含量的金属螯合肽。 PYC几乎存在于任何人类饮食中，但人体中的功能是未研究的。植物中详细介绍的PYC-CD相互作用以及初步 PYC在人类尿液中的发现，导致假设饮食中的Pyc可以干预饮食CD 动物系统。这将通过使用多种OMICS技术和评估技术来测试氧化还原生物学和男性生育能力和生殖健康的多种措施。 AIM 1将确定通过使用高分辨率代谢组和一个同位素标记的示踪剂，PYC处理对金属分布的影响将通过使用高分辨率代谢组学和金属学。 AIM 2将确定PYC给药的影响通过分析氧化还原电位和抗氧化剂活性的分析，CD在男性生殖系统中暴露以及多词（代谢组学，金属学和表观基因组学）的生殖组织分析除了评估生育能力，精子质量和组织病理学。这些实验将产生关键饮食CD对保护男性复制健康的氧化还原系统的影响的综合轨迹，它们将导致改善受CD强大影响的人群的一般和生殖健康的干预措施通过证明饮食中的植物挑替肽作为人类的金属排毒剂来暴露。