Genetic Factor Lowers Threshold of Mercury Toxicity in Humans

By Tingting Li, Environmental and Occupational Health Sciences

Tingting Li

Mercury is naturally present in our environment, and it is very toxic. In 1999, the Agency for Toxic Substances and Disease Registry (ATSDR) at the CDC issued a public health statement on mercury, stating that dental amalgam was a major source of elemental mercury exposure in the general population. Other common sources of elemental mercury exposure are certain occupations, such as those involved with the use, production, or transportation of mercury, gold, or dental amalgam; household products such as batteries, thermostats, fluorescent lights, and thermometers; and contaminated air near coal-burning power plants.

Previous studies have shown that chronic exposure to elemental mercury, especially as mercury vapor, is associated with neuropsychiatric disorders such as attention- and concentration-deficits, memory loss, and depression. Even very low levels of mercury vapor exposure may elicit adverse behavioral effects. Moreover, some people may be uniquely susceptible to mercury vapor-mediated neurological deficits because of a genetic predisposition.

For my Ph.D. dissertation research, I worked with professor James Woods in DEOHS to examine how genetic variations lower a person’s threshold for mercury toxicity by affecting the same processes in the central nervous system (CNS) that are known to be impaired by mercury. One such variant, CPOX4, is a mutation of the gene encoding coproporphyrinogen oxidase (CPOX), one of the enzymes in the formation of heme, a molecule that is required for cellular energy production and the formation of neurotransmitters in the brain.

We characterized the enzymes from human subjects with wild type (CPOX) and mutated (CPOX4) genes in terms of how they regulate enzymatic reactions, how mercury inhibits the catalytic reactions, and how they affect heme synthesis both in vitro, in human livers, and in cell models. We found that the CPOX4 enzyme had lower activity and binds to substrate less tightly, which first leads to insufficient heme synthesis and further results in diminished neurotransmitter formation and capacity for neurobehavioral performance.

We also evaluated the potential adverse effects of chronic mercury exposure from dental amalgams on CNS function in older vulnerable adults and found that lifetime exposure to mercury dental amalgam, even though at an extremely low level, may increase the risk of memory loss in addition to the loss associated with aging in the elderly.

Given the relatively high frequency of this CPOX4 variant genotype in the general population (25% heterozygous and 2% homozygous) and the extensive presence of mercury in the environment, my research is of substantial public importance, particularly for risk assessment and risk prevention of mercury exposure to genetically susceptible subjects.