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

项目摘要 近几十年来，男性生育率一直在下降，这部分是由于大量的 人类每天都会接触到的环境。其中，重金属镉（Cd）是一个值得注意的问题。 存在于空气、饮用水和饮食中的多种成分中的男性生殖毒物，以及 平均每人每天通过饮食接触30微克。镉是有毒的通过一些机制， 但其作用主要是通过产生氧化应激和干扰抗氧化剂而引起的 的防御合作.植物系统通过产生植物螯合素来处理有毒的镉和其他重金属暴露 （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，但它们的 在人体内的功能尚未研究。PyC-Cd相互作用在植物中的详细描述，沿着初步的 人类尿液中PyC的发现，导致饮食PyC可以干预饮食Cd的假设， 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项措施。目标1将决定 通过使用高分辨率代谢组学和一种新的方法， 同位素标记的示踪剂，以及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组学。目标2将确定PyC给药的效果， 通过氧化还原电位和抗氧化酶活性分析男性生殖系统中的镉暴露 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 以及生育力、精子质量和组织病理学的评估。这些实验将产生关键的 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， 将采取干预措施，改善受镉严重影响的人群的一般健康和生殖健康 通过证明饮食中的植物螯合素作为人体中的金属解毒剂，

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.