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

MERCURY 275
2. HEALTH EFFECTS
(thought to be associated with the B-cell proliferation) (Hirsch et al. 1982; Matsuo et al. 1989), and marked
increases in serum levels of IgE (Dubey et al. 1991b; Hirsch et al. 1986; Lymberi et al. 1986; Prouvost-Danon
et al. 1981). Increases in the production of autoantibodies (IgG) to glomerular basement membrane,
thyroglobulin, collagen types I and II, and DNA also occur (Pusey et al. 1990). Immune complex deposits
occur in blood vessels in several organs (Hultman et al. 1992), and deposition of these autoantibodies and
complement in the renal glomerulus ultimately lead to membranous glomerulonephropathy, although the
deposition of the IgG alone does not appear to be sufficient to induce renal dysfunction (Michaelson et al.
1985). In rodents, the autoimmune response spontaneously resolves within a few weeks. The mechanism
underlying the resolution is unknown, but antiidiotypic antibodies and a change in the balance between Th2
and Th1 (another subset of the CD4+ T-cells) cell activation (see below) have been proposed (Mathieson
1992). After this resolution phase has occurred, affected individuals develop a resistance to future
autoimmune toxicity (Bowman et al. 1984). The resistance appears to be mediated by CD8+ T-cells, since
depletion of these cells reverses the resistance (Mathieson et al. 1991).
The so-called resistant strains, however, show a different response to mercury exposure. These resistant
strains also show an increase in MHC expression molecules on B-cells, but this response is extremely shortlived,
and increases in serum IgE were not observed (Dubey et al. 1991a; Prouvost-Danon et al. 1981). The
difference in the responses of the so-called resistant and susceptible strains may be found in the activation of
Th1 cells and the increase in secretion of γ-interferon by the Th1 cells of resistant animals (van der Meide et
al. 1993). The susceptible strains do not show an increase in γ-interferon production with mercury exposure.
Because γ-interferon inhibits the proliferation of Th2 cells, the absence of this response in the susceptible
strains may allow the Th2 cell-stimulated production of autoantibodies to occur, whereas in the resistant
strains the production of antibodies is curtailed. Thus, differences in the activation of Th1 versus Th2 cells
may underlie the differences in susceptibility of various individuals. Studies using in-bred strains of mice and
rats have determined that the susceptibility to the different immune reactions is governed by both MHC genes
as well as other genes (Aten et al. 1991; Druet et al. 1977; Mirtcheva et al. 1989; Sapin et al. 1984). As
indicated in the section on renal effects, Brown-Norway, MAXX, and DZB rat strains showed susceptibility,
whereas Lewis, M520, and AO rats did not (Aten et al. 1991; Druet et al. 1978; Michaelson et al. 1985).
Among mouse strains, SJL/N mice are susceptible and DBA, C57BL, and Balb/c mice are not (Hultman and
Enestrom 1992; Hultman et al. 1992). In a resistant strain, the Balb/c mouse, immune suppression was
manifested as decreased natural killer cell activity in mice administered a diet containing 0.5 mg Hg/kg/day as
methylmercury (Ilback 1991).