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

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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.