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

MERCURY 215
2. HEALTH EFFECTS
organization and a distorted alignment of neurons in the cerebral cortex. Exposures first occurred during
the critical period of neuronal migration (from gestation week 7 into the third trimester) in the fetus. Both
could result from a direct effect of mercury on microtubule proteins. Cell division and cell migration both
require intact microtubules for normal functioning and, therefore, have been suggested as primary targets
for methylmercury disruption in the developing nervous system. It is hypothesized by Aschner and
Clarkson (1988) that the uptake of methylmercury through the blood-brain barrier in developing and mature
animals is closely linked to amino acid transport and metabolism because of the infusion of L-cysteine
enhanced 203 Hg uptake. The enhanced transport in the fetus may be a result of the immaturity of the
transport systems in the blood-brain barrier or of possible physical immaturity of the barrier itself. Methylmercury
has also been shown to increase intracellular Ca ++ and inositol phosphate levels (Sarafian 1993).
The observed stimulation of protein phosphorylation in rat cerebral neuronal culture was believed to be the
result of elevation of intracellular second messengers (Ca ++ , inositol phosphate) rather than to a direct
interaction between methylmercury and protein kinase enzymes. This observation was considered to
suggest a specific interference with neuronal signal transduction.
The mercuric ion is also an extremely potent inhibitor of microtubule polymerization, both in vivo and in
vitro (Duhr et al. 1993). Duhr and his colleagues further reported that the ability of Hg ++ to inhibit
microtubule polymerization or to disrupt already formed microtubules not only cannot be prevented by
binding with the chelating agents EDTA and EGTA, but that the binding of these two potent chelators
potentiates the Hg ++ -induced inhibition of tubulin polymerization by disrupting the interaction of GTP with
the E-site of brain beta-tubulin, an obligatory step in the polymerization of tubulin.
Mercury has been shown to inhibit a variety of enzymes in the nervous system. The effects of mercuric
chloride and methylmercuric chloride on the activity of protein kinase C in rat brain homogenate were
studied by Rajanna et al. (1995). In this study, it was found that both forms of mercury inhibited protein
kinase C activity in a dose-dependent manner at micromolar concentrations, with methylmercury being a
more potent inhibitor than HgCl2. Mercuric chloride has also been shown to cause the inhibition and
ultrastructural localization of cerebral alkaline phosphatase (Albrecht et al. 1994) following a single
intraperitoneal injection of 6 mg HgCl2/kg body weight. The observed inhibition and subsequent
translocation of alkaline phosphatase activity from the luminal to abluminal site and the accompanying
ultrastructural alterations were reported to be typical of the formation of "leaky" microvessels known to be
associated with damage to the blood-brain barrier. Mercuric chloride has also been demonstrated to block
the uptake of [3H]-histamine by cultured rat astroglial cells and brain endothelial cells (Huszti and Balogh