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

MERCURY 210
2. HEALTH EFFECTS
Strain and sex differences in renal mercury content in mice are attributable, in part, to differences in tissue
glutathione content and to differences in renal γ-glutamyltranspeptidase activity, which is controlled, at
least in part, by testosterone (Tanaka et al. 1991, 1992). The correlation of hepatic glutathione (or plasma
glutathione) with the rate of renal uptake of methylmercury suggests that methylmercury is transported to
the kidneys as a glutathione complex (Tanaka et al. 1991). In addition to strain and sex differences in renal
mercury content, it has also been demonstrated using mice (133–904 days old) that the ratio of mercury in
the brain to that in the liver and the kidneys increased significantly with age (Massie et al. 1993).
In a study of the absorption of inorganic mercury by the rat jejunum, Foulkes and Bergman (1993) found
that while tissue mercury could not be rigorously separated into membrane-bound and intracellular
compartments (as can the heavy metal cadmium), its uptake into the jejunum includes a relatively
temperature-insensitive and rapid influx into a pool readily accessible to suitable extracellular chelators. A
separate, slower and more temperature-sensitive component, however, leads to the filling of a relatively
chelation-resistant compartment. Nonspecific membrane properties, such as surface charge or membrane
fluidity, might account for mucosal mercury uptake (Foulkes and Bergman 1993).
2.4.2 Mechanisms of Toxicity
High-affinity binding of the divalent mercuric ion to thiol or sulfhydryl groups of proteins is believed to be
a major mechanism for the biological activity of mercury (Clarkson 1972a; Hughes 1957; Passow et al.
1961). Because proteins containing sulfhydryl groups occur in both extracellular and intracellular
membranes and organelles, and because most sulfhydryl groups play an integral part in the structure or
function of most proteins, the precise target(s) for mercury is not easily determined, if indeed there is a
specific target. Possibilities include the inactivation of various enzymes, structural proteins, or transport
processes (Bulger 1986); or alteration of cell membrane permeability by the formation of mercaptides
(Sahaphong and Trump 1971). Binding may also occur to other sites (e.g., amine, carboxyl groups) that are
less favored than sulfhydryl groups. A variety of mercury-induced alterations are being investigated,
including increased oxidative stress, disruption of microtubule formation, increased permeability of the
blood-brain barrier, disruption of protein synthesis, disruption of DNA replication and DNA polymerase
activity, impairment of synaptic transmission, membrane disruption, impairment of the immune response,
and disruption in calcium homeostasis. These alterations may be acting singly or in combination.