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<br>Display Omitted<br>• Mercuric chloride-human serum albumin adduct causes hormesis in N9 microglia cells. • Hormesis was implemented through ERK/MAPKs and JAK/STAT3 signaling pathways. • 15 ng/mL of Hg-HSA was close to a NOAEL for N9 cells and this dose may be beneficial. • Hg2+ could form stable coordination structures in both Asp249 site and Cys34 site of HSA.<br>Mercury chloride (HgCl2), a neurotoxicant that cannot penetrate the blood-brain barrier (BBB). Although when the BBB are got damaged by neurodegenerative disorders, the absorbed HgCl2, mainly in form of Hg (II)-serum albumin adduct (Hg-HSA) in human plasma, can penetrate BBB and affect central nervous system (CNS) cells. Current study planned to evaluate the effect of Hg-HSA on the physiological function of N9 microglial cells. At low dosage (15 ng/mL) of Hg-HAS, the observed outcomes was: promoted cell propagation, Nitric Oxide (NO) and intracellular Ca2+ levels enhancement, suppressed the release of TNF-α and IL-1β and inhibited cell proliferation. At high dosage (15 μg/mL) we observed decline in NO and intracellular Ca2+ levels, and increment in the release of TNF-α and IL-1β. These biphasic effects are similar to hormesis, and the hormesis, in this case, was executed through ERK/MAPKs and JAK/STAT3 signaling pathways. Study of quantum chemistry revealed that Hg2+ could form stable coordination structures in both Asp249 and Cys34 sites of HSA. Although five-coordination structure in Asp249 site is more stable than four-coordination structure in Cys34 site but four-coordination structure is formed easily in-<b>vivo</b> in consideration of binding-site position in spatial structure of HSA.
Methylmercury (MeHg+) is an extremely toxic organomercury cation that can induce severe neurological damage. Once it enters the body, methylmercury binds to amino acids or proteins containing free sulfhydryl groups. In particular, methylmercury is known to bind with human serum albumin (HSA) in human plasma; however, the effects of methylmercury-HSA conjugate (MeHg-HSA) on the central nervous system (CNS) are not fully understood. In the present study, we used the microglial cell line N9 as the target cells to evaluate the effect of MeHg-HSA on physiological function of the CNS preliminarily. The various factors in the cell culture were monitored by MTT assay, total lactate dehydrogenase assay, ELISA, qPCR, Western blot and flow cytometry techniques. The results showed that low-dose treatment with MeHg-HSA activated N9 cells, promoting cell proliferation and total cell number, enhancing NO and intracellular Ca2+ levels, and suppressing the release of TNFα and IL1β without cytotoxic effects; while high-dose MeHg-HSA exhibited cytotoxic effects on N9 cells, including promoting cell death and increasing the secretion of TNFα and IL1β. These results indicate that MeHg-HSA causes hormesis in microglia N9 cells. Furthermore, ERK/MAPKs and STAT3 signaling pathways related to the hormesis of MeHg-HSA on N9 cells. In addition, low dose of MeHg-HSA might be viewed as something very close to a lowest observed adverse effect level (LOAEL) for N9 cells. These findings will be useful for investigating the hormesis mechanism of MeHg+ and exploring the specific functions of MeHg-sulfhydryl conjugates on the central nervous system.