THE EFFECT OF TOXICOKINETICS ON MURINE MERCURY-INDUCED AUTOIMMUNITY

Mercury induces autoantibodies to the nucleolar protein fibrillarin (A NoA) in genetically susceptible (H-2A(s)) mouse strains. This study ex amines the importance of mercury toxicokinetics for the induction and strength (titer) of these autoantibodies. Female mice of the inbred st rains A.SW and B10.S (H-2A(s) on the A and C57BL/10 genetic background , respectively) and A.TL and B10.TL (B-2A(k) on the A and C57BL/10 bac kground) were treated with (HgCl2)-Hg-203 in a dose of 1, 5, or 16 mg Hg/L drinking water for 56-70 days. Whole-body retention of Hg-203 was monitored throughout the experimental period. Mercury accumulation in kidney, liver, heart, spleen, and brain was determined at end of the experiment when blood samples were also obtained for determination of ANoA. The drinking water consumption showed a limited variation betwee n the strains and the dose groups. Therefore, intake of mercury did no t vary much between the strains at a given dose level. The whole-body retention of mercury reached steady state after 4-5 weeks. In general, the B10.S and B10.TL strains showed a lower whole-body retention and deposition of mercury in the kidney and the liver, compared with the A .SW and A.TL strains given the same dose of mercury. The B10.S strain showed a threshold for induction of ANoA at 5 mg Hg/L, whereas ANoA we re still seen in A.SW mice given 1 mgHg/L. Taken together, this is com patible with a less efficient elimination of mercury in the A.SW and A .TL strains, which was also supported by the higher ratio between whol e-body retention and intake of mercury in these strains. These finding s indicate that genes residing outside the H-2 (MHC) complex play an i mportant role for regulating mercury toxicokinetics, the A genes confe rring higher accumulation of mercury in the body than the B10 genes. I n mice congenic with regard to the susceptible H-2A(s) haplotype, a hi ghly significant correlation (P < 0.01) existed between on the one han d the whole-body retention and organ accumulation of mercury and on th e other hand the titer of ANoA. We conclude that mercury toxicokinetic s differs significantly among inbred mouse strains. The differences in toxicokinetics are regulated by non-H-2 genes and correlate with the autoimmune response in the genetically susceptible strains: quantitati vely as the titer of the ANoA and qualitatively as different threshold doses for induction of ANoA by mercury. (C) 1998 Academic Press.