| Author | Tawit Suriyo |
| Call Number | AIT Diss. no.EV-08-5 |
| Subject(s) | Methylmercury--Environmental aspects
|
| Note | A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Environmental Engineering and Management Inter-University Program on Environmen tal Toxicology, Technology and Management |
| Publisher | Asian Institute of Technology |
| Series Statement | Dissertation ; no. EV-08-5 |
| Abstract | Methylmercury (MeHg) is an environmental toxicant that is known to induce immune system alteration; however, little is known about the molecular mechanism involved. Neuronal cholinergic system has been postulated to be an important target of MeHg toxicity. Following the discovery of the non-neuronal cholinergic system in lymphocytes which is involved in the regulation of immune functions, the immunotoxic effects of McHg with special emphasis on the role of non-neuronal lymphocytic cholinergic system were investigated in this study. The in vivo study in mice showed that oral exposure to low dose of MeHg 2.5 or 5 mg/kg/day for 14 days significantly produced an up-regulation of splenic muscarinic acetylcholine receptor (mAChR) subtype M3 expression and also altered the immune system. The alteration were increased weight of immune organs (spleen and thymus), and the increase in the number of total white blood cells in blood circulation. For the increase of the total white blood cell numbers, the study identified that the granulocyte and monocyte subsets were increased, while the lymphocytes subset was not changed. The in vitro study in human leukemic T-cells showed that MOLT-3 cells were more sensitive to McHg-induced cytotoxic effects than Jurkat clone E6-1 cells, suggesting that the lymphocytic muscarinic cholinergic system may be involved since the expression of five subtypes [Ml-M5] of mAChR in MOLT-3 cells were higher than in Jurkat cells. The role of mAChR-linked pathways in McHg-induced apoptosis in human leukemic Tcells was examined in this study. Treatment of the MOLT-3 cells with 1 M of MeHg produced induction of c-Fos gene expression, apoptotic cell death, and down-regulation of mAChR. McHg-induced c-Fos gene expression was significantly reduced by pretreatment with atropine (a non-selective mAChR antagonist), or 4-DAMP (a selective M1/M3 mAChR antagonist), whereas pirenzipine (a selective Ml mAChR antagonist), or himbazine (a selective M2/M4 mAChR antagonist) slightly reduced this induction, suggesting that activation of the M3 mAChR by McHg controls the expression of c-Fos gene. Pretreatment with 4-DAMP or SB 203580 (a specific p38 inhibitor) resulted in decreases in the level of phosphorylated p38, c-Fos gene expression, and apoptotic cell death induced by MeHg. Taken together, these data suggest that the M3 mAChR-p38-dependent pathway participates in the increase of c-Fos gene expression, which is involved in MeHg-induced lymphocyte apoptosis. In addition, a noncytotoxic concentration of McHg (0.1 uM) inhibited PHAIPMA-stimulated IL-2 production, and this inhibition was reversed by pretreatment with atropine or 4-DAMP. Overall, this study provides initial evidence that MeHg may alter the immune system by targeting the lymphocytic mAChR |
| Year | 2008 |
| Corresponding Series Added Entry | Asian Institute of Technology. Dissertation ; no. EV-08-5 |
| Type | Dissertation |
| School | School of Environment, Resources, and Development (SERD) |
| Department | Department of Energy and Climate Change (Former title: Department of Energy, Environment, and Climate Change (DEECC)) |
| Academic Program/FoS | Environmental Engineering and Management (EV) |
| Chairperson(s) | Jutamaad Satayavivad ;Preeda Parkpian (Co-Chairperson) ;Sansanee Chaiyaroj (Co-Chairperson) |
| Examination Committee(s) | Apinya Thiantanawa |
| Scholarship Donor(s) | Chulabhorn Research Institute ;Mahidol University ;Asian Institute of Technology Fellowship |
| Degree | Thesis (Ph.D.) - Asian Institute of Technology - Chulabhorn Research Institute - Mahidol University, 2008 |