Immunosuppressive and autoimmune effects of thimerosal in mice
2005 (English)In: TOXICOLOGY AND APPLIED PHARMACOLOGY, ISSN 0041-008X, Vol. 204, no 2, 109-21 p.Article in journal (Refereed) Published
The possible health effects of the organic mercury compound thimerosal (ethylmercurithiosalicylate), which is rapidly metabolized to ethylmercury (EtHg), have recently been much debated and the effect of this compound on the immune system is largely unknown. We therefore studied the effect of thimerosal by treating A.SW (H-2(s)) mice, susceptible to induction of autoimmunity by heavy metals, with 10 mg thimerosal/L drinking water (internal dose ca 590 mu g Hg/kg body weight/day) for up to 30 days. The lymph node expression of IL-2 and IL-15 mRNA was increased after 2 days, and of IL-4 and IFN-gamma rnRNA after 6 and 14 days. During the first 14 days treatment, the number of splenocytes, including T and B cells as well as Ig-secreting cells decreased. A strong immunostimulation superseded after 30 days treatment xvith increase in splenic weight, number of splenocytes including T and B cells and Ig-secreting cells, and Th2- as well as Th-l-dependent serum immunoglobulins. Antinucleolar antibodies (ANoA) targeting the 34-kDa nucleolar protein fibrillarin, and systemic immune-complex deposits developed. The H-2(s) strains SJL and B10.S also responded to thimerosal treatment with ANoA. The A.TL and B10.TL strain, sharing background genes with the A.SW and B10.S strain, respectively, but with a different H-2 haplotype (tl), did not develop ANoA, linking the susceptibility to H-2. Thimerosal-treated H-2(s) mice homozygous for the nu mutation (SJL-nu/nu), or lacking the T-cell costimulatory molecule CD28 (B10.S-CD28(-/-)), did not develop ANoA, which showed that the autoimmune response is T-cell dependent. Using H-2(s) strains with targeted mutations, we found that IFN-gamma and IL-6, but not IL-4, is important for induction of ANoA by thimerosal. The maximum added renal concentration of thimerosal (EtHg) and inorganic mercury occurred after 14 days treatment and was 8 1 mu g Hg/g. EtHg made tip 59% and inorganic mercury 41% of the renal mercury. In conclusion, the organic mercury compound thimerosal (EtHg) has initial immunosuppressive effects similar to those of MeHg. However, in contrast to MeHg, thimerosal treatment leads in genetically susceptible mice to a second phase with strong immunostimulation and autoimmunity, which is T-cell dependent, H-2 linked and may at least partly be due to the inorganic mercury derived from the metabolism of ethyl mercury.
Place, publisher, year, edition, pages
2005. Vol. 204, no 2, 109-21 p.
thimerosal, ethylmercury, mice, immunosuppression, autoimmunity
IdentifiersURN: urn:nbn:se:umu:diva-13583DOI: doi:10.1016/j.taap.2004.08.019OAI: oai:DiVA.org:umu-13583DiVA: diva2:153254