Project title: Coproporphyrinogen Oxidase (CPOX) Polymorphism in Human Mercury Neurotoxicity
Completed in: 2009
Mercury (Hg) is a known neurotoxicant in humans. In previous studies, we identified a specific polymorphism (A814C) in exon 4 of the human CPOX gene (CPOX4) and demonstrated that CPOX4 significantly increases the effect of Hg on urinary porphyrin excretion and also adversely modifies the effect of Hg on a wide range of neurobehavioral functions. To further investigate the biochemical properties and basis of Hg susceptibility associated with this polymorphism, we cloned and expressed human CPOX and CPOX4 genes in vitro and characterized the biochemical properties of the purified proteins. Findings demonstrated that CPOX4 expresses less than half the activity of CPOX and that this is further limited by Hg exposure both in vitro and in human livers. Additionally, we acquired blood samples from human subjects and employed Epstein Barr viral transformation to establish cell CPOX and CPOX4 lines and found that CPOX4 cells were more susceptible to heme deficiency related cell death. Moreover, we examined the potential effects of the CPOX4 polymorphism on the association between dental amalgam derived mercury exposure and neurobehavioral domains and psychosocial scales in older adults. At very low levels of Hg exposure, convincing associations were only observed for expected Hg-related deficits for declarative memory and depression in both genders replicating previously observed deficits in these abilities in occupationally exposed adults. Associations with CPOX4 were sparse and in scores unrelated with Hg exposure precluding detection of an interaction. Future studies in older adults would benefit by ascertaining total mercury measured in blood and in urine.