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

• 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
• 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

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.

项目总结 近几十年来，男性生育率一直在下降，这在一定程度上是由于 人类每天都会遇到环境暴露。其中，重金属镉(Cd)是值得注意的 空气、饮用水和饮食中的许多成分中存在的雄性生殖毒物，以及 平均每人每天通过饮食摄入30微克。Cd是有毒的，通过多种机制， 但它的大部分影响是通过产生氧化应激和干扰抗氧化剂而产生的 防御。植物系统通过产生植物络合素来应对有毒的Cd和其他重金属暴露 (PYCS)是一种硫醇含量较高的金属螯合肽。PYC几乎存在于任何人类饮食中，但它们的 在人体内的功能还未被研究。PYC-Cd相互作用在植物中的详细描述，以及初步的 人体尿中PYC的发现，导致假设饮食PYC可以干预饮食Cd在一个 动物系统。这将通过使用多种组学技术以及评估技术进行测试 氧化还原生物学和男性生育力和生殖健康的多种衡量标准。目标1将决定 应用高分辨代谢组学和核磁共振技术研究PYCs在小鼠模型中的代谢和分布 同位素标记的示踪剂，以及热解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组学。目标2将确定PYC管理的效果 男性生殖系统镉暴露的氧化还原电位和抗氧化酶活性分析 以及生殖组织的多组学(代谢组学、金属组学和表观基因组学)分析 同时对生育力、精子质量和组织病理学进行评估。这些实验将产生关键的 关于膳食镉对保护男性生殖健康的氧化还原系统的影响的综合组学，以及它们 将采取干预措施，改善受CD严重影响的人群的一般健康和生殖健康 通过展示饮食中的植物螯合素作为金属解毒剂在人类中的暴露。