One of the most well-characterized symptoms of lead poisoning is porphyria. The biochemical signs of lead intoxication related to porphyria are δ-aminolevulinic aciduria, coproporphyrinuria, and accumulation of free and zinc protoporphyrin in erythrocytes. From the 1970s to the early 80s, almost all of the enzymes in the heme pathway had been purified and characterized, and it was demonstrated that δ-aminolevulinic aciduria is due to inhibition of δ-aminolevulinate dehydratase by lead. Lead also inhibits purified ferrochelatase; however, the magnitude of inhibition was essentially nil even under pathological conditions. Further study proved the disturbance of iron-reducing activity by moderate lead exposure. Far different from these two enzymes, lead failed to inhibit purified coproporphyrinogen oxidase, i.e., the mechanism of coproporphyrinuria has not yet been understood. During the 80s to the 90s, the effects of environmental hazards including lead were elucidated through stress proteins, indicating the induction of some heme pathway enzymes as stress proteins. At that time, gene environment interaction was another focus of toxicology, since gene carriers of porphyrias are considered to be a high-risk group to chemical pollutants. Toxicological studies from the 70s to the 90s focused on the direct effect of hazards on biological molecules, such as the heme pathway enzymes, and many environmental pollutants were proved to affect cytosolic heme. Recently, we demonstrated the mechanism of the heme-controlled transcription system, which suggests that the indirect effects of environmental hazards are also important for elucidating toxicity, i.e., the hazards can affect cell functions through such biological mediators as regulatory heme. It is, therefore, probable that toxicology in the future will focus on biological systems such as gene regulation and signal transduction systems.
Methylmercury is a known pollutant that causes severe central nervous system disorders. It is capable of passing through the blood-brain barrier and accumulates in cerebral cells. However, little is known regarding the mechanism of its toxicity at the molecular level. Using yeast cells, we searched for the genes involved in the expression of methylmercury toxicity, and found that genes encoding L-glutamine·D-fractose-6-phosphate amidotransferase (GFAT) and ubiquitin transferase (Ubc3) confer methylmercury resistance on the cells. It has also been shown that GFAT is the target molecule of methylmercury in yeast cells. These findings provide important clues about the mechanism underlying methylmercury toxicity ini mammals.
The interaction between mercury and selenium may involve a variety of toxicologically and biochemically distinct processes. In this paper, the interaction between inorganic mercury and sodium selenite, the interaction most extensively studied, as well as the interaction between methylmercury (MeHg) and selenium, the interaction perhaps most significant for non-occupational human populations, will be discussed. It has been shown that the former interaction can be understood as a modification of the kinetic behavior of inorganic mercury by selenite, but this interaction may occur only under very limited conditions. On the other hand, the mechanism of the latter interaction is largely unknown, and kinetic modification appears to play only a minor role. An interaction between MeHg and selenoproteins or a possible interaction between the inorganic mercury, resulting from the demethylation of MeHg, and the selenium may be important. Compared to the experimental findings, little evidence of the toxicological modification of MeHg by selenium was obtained in epidemiological studies.
Mercury vapor is known penetrate the placental barrier more easily than inorganic mercury. A relative amount of mercury accumulates in the fetus after exposure of pregnant animals to mercury vapor. Mercury concentration in fetal organs is much lower than that in maternal organs except the liver, and fetal liver shows significantly higher mercury concentrations than maternal liver. In fetal liver, a substantial portion of mercury is bound to metallothionein (MT), which plays an important role as a reservoir of mercury during the prenatal period. The mercury retained in fetal liver is redistributed to other organs, such as the brain and kidney, with diminishing MT levels during postnatal development. Consequently, an increase in mercury concentration in the brain and kidney of the neonate is observed. In studies on animal offspring in utero exposed to mercury vapor, behavioral changes, such as radial arm maze, morris maze and lever-press durations, are observed when the levels of mercury vapor exceed the threshold limit value (TLV).
Adverse health effects following prenatal exposures to methylmercury (MeHg) have been apparent from several prospective cohort studies conducted in a fish-eating population. A prospective study in a Faroese birth cohort documented subtle deficits of several functional domains at prenatal MeHg exposure levels previously thought to be safe. Recent additional studies also showed neurobehavioral deficits associated with exposures to polychlorinated biphenyls (PCBs) with concomitant MeHg poisoning. In contrast, a prospective study in the Seychelles did not detect a similar association between MeHg exposure and neurodevelopmental deficits; children of the highest MeHg exposure group showed better scores in some developmental tests than those of the lower exposure groups for both prenatal and postnatal MeHg exposures. This paradoxical difference between both studies is summarized herein. The primary source of human exposure to MeHg is fish. Since a considerable number of pollutants, including polychlorinated biphenyls (PCBs) and pesticides, are also present in fish, and since some organochemical substances including PCBs are also well documented to be neurotoxic to the developing brain from epidemiological studies, the combined effects of these pollutants should be considered in discussing the neurotoxicity of MeHg. In this article, therefore, major prospective cohort studies focusing on the exposures to PCBs were reviewed.