revised final - Agency for Toxic Substances and Disease Registry ...

MERCURY 214
2. HEALTH EFFECTS
Recent data from an in vitro study suggest that mercuric mercury may be more effective than methyl­
mercury in some paradigms. Using patch-clamped dorsal root neurons, Arakawa et al. (1991) showed
augmentation of the GABA-activated chloride current at extremely low mercuric chloride concentrations
(0.1 µM), while a 1,000-fold higher concentration of methylmercury showed no such effect. The
correlation between these effects observed in vitro and what may be occurring in vivo, however, is not
known.
The experimental data concerning the mechanism of action of methylmercury on the developing nervous
system indicate that effects on the microtubules and amino acid transport are disrupted in neuronal cells
before overt signs of intoxication are observed. Vogel et al. (1985) demonstrated the potent inhibitory
effects of methylmercury on microtubule assembly at ratios stoichiometric with the tubulin dimer. The
effects were thought to be mediated through MeHg binding to free sulfhydryl groups on both ends and on
the surface of microtubules, which would provide multiple classes of binding sites for MeHg. In
subsequent in vitro studies, Vogel et al. (1989) identified a single high affinity class of binding sites on
tubulin for methylmercury with 15 sites. The authors report that MeHg binds to tubulin stoichiometrically
within microtubules, and does not induce microtubule disassembly at this low binding ratio. Free subunits
of tubulin, however, will act as uncompetitive inhibitors for MeHg binding to the polymer, and MeHg
binding to the multiple sites in the free dimer blocks subsequent assembly. In contrast, the stoichiometric
polymer surface binding sites for MeHg in microtubules apparently do not interfere with subsequent
polymerization. Mitotic inhibition from damage to microtubulin and binding to tubulin has also been
reported by Sager et al. (1983).
Comparison of the effects of mercury on structural elements and enzyme activities (Vignani et al. 1992)
suggests that effects on cytoskeletal elements may be observed at lower concentrations than on enzyme
activities. In the in vivo study by Sager et al. (1982), it was concluded that methylmercury may be acting
on mitotic spindle microtubules leading to cell injury in the developing cerebellar cortex. Cell injury
observed in the external granular layer of the cerebellar cortex of 2-day-old rats was attributed to a reduced
percentage of late mitotic figures (arrested cell division) due to the loss of spindle microtubules. Mitosis
and migration of granule cells in the cerebellum end within weeks following birth; therefore, this
observation may suggest potential differences in the sensitivities of children and adults to mercury-induced
neurotoxicity. The toxic effects of methylmercury on the developing nervous system may also be due to
deranged neuronal cell migration (Choi et al. 1978; Matsumoto et al. 1965). Examination of the brains of
two infants who died following in utero exposure to methylmercury revealed an abnormal pattern in the