The effect of toxicokinetics on murine mercury-induced autoimmunity.
Mercury induces autoantibodies to the nucleolar protein fibrillarin (ANoA) in genetically susceptible (H-2AS) mouse strains. This study examines the importance of mercury toxicokinetics for the induction and strength (titer) of these autoantibodies. Female mice of the inbred strains A.SW and B10.S (H-2AS on the A and C57BL/10 genetic background, respectively) and A.TL and B10.TL (H-2Ak on the A and C57BL/10 background) were treated with 203HgCl2 in a dose of 1, 5, or 16 mg Hg/L drinking water for 56-70 days. Whole-body retention of 203Hg 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 between the strains and the dose groups. Therefore, intake of mercury did not 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 were still seen in A.SW mice given 1 mg Hg/L. Taken together, this is compatible with a less efficient elimination of mercury in the A.SW and A.TL strains, which was also supported by the higher ratio between whole-body retention and intake of mercury in these strains. These findings indicate that genes residing outside the H-2 (MHC) complex play an important role for regulating mercury toxicokinetics, the A genes conferring higher accumulation of mercury in the body than the B10 genes. In mice congenic with regard to the susceptible H-2AS haplotype, a highly significant correlation (P<0.01) existed between on the one hand the whole-body retention and organ accumulation of mercury and on the other hand the titer of ANoA. We conclude that mercury toxicokinetics 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: quantitatively as the titer of the ANoA and qualitatively as different threshold doses for induction of ANoA by mercury.
Hultman
P
P
Department of Health and Environment, Linköping University, Linköping, Sweden.
Nielsen
J B
JB
D000818:Animals; D001323:Autoantibodies / Q000187:drug effects / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity / Q000187:drug effects*; D002868:Chromosomal Proteins, Non-Histone / Q000187:drug effects / Q000276:immunology; D004198:Disease Susceptibility / Q000276:immunology / Q000378:metabolism; D004202:Disinfectants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004326:Drinking; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006183:H-2 Antigens / Q000187:drug effects / Q000235:genetics; D008627:Mercuric Chloride / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D008628:Mercury / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D008631:Mercury Radioisotopes; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D011834:Radiation Monitoring; D012261:Ribonucleoproteins / Q000187:drug effects / Q000276:immunology; D012996:Solutions / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D013045:Species Specificity; D014018:Tissue Distribution
D001323:Autoantibodies; D002868:Chromosomal Proteins, Non-Histone; D004202:Disinfectants; D006183:H-2 Antigens; D008631:Mercury Radioisotopes; D012261:Ribonucleoproteins; D012996:Solutions; C047458:fibrillarin; D008627:Mercuric Chloride; D008628:Mercury