title: Autoantibodies to neurotypic and gliotypic proteins as biomarkers of neurotoxicity: assessment of trimethyltin (TMT).
abstract: Developing accessible biomarkers of neurotoxic effects which are readily applicable to human populations poses a challenge for neurotoxicology. In the past, the neurotoxic organometal trimethyltin (TMT) has been used as a denervation tool to validate the enhanced expression of GFAP as a biomarker of astrogliosis and neurotoxicity resulting from chemical exposures. In the present study, TMT was used to assess the detection of serum autoantibodies as biomarkers of neurotoxicity. Previous studies in both human and animals have demonstrated the presence of serum autoantibodies to neurotypic [e.g., neurofilament triplet (NF)] and gliotypic proteins [myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP)] as a peripheral marker of neurodegeneration that may be applicable to humans and experimental studies. Male Long-Evans rats (45 days of age) were administered either TMT (8 mg/kg; s) or an equal volume of sterile 0.9% saline. At 1, 2, and 3 weeks post-administration, serum was collected, and rats were sacrificed for the collection of brains. Serum autoantibodies (both IgM and IgG isotypes) to NF68, NF160, NF200, MBP, and GFAP were assayed using an ELISA. Saline only rats did not have detectable levels of autoantibodies. Only sera from TMT-exposed rats had detectable titers of autoantibodies to NFs with IgG predominating starting week 2. Anti-NF68 titers were highest compared to NF160, or NF200. Autoantibodies to MBP and GFAP also were detected; however, there was no significant increase in their titers until week 3. Hippocampal GFAP, detected at these time points, was significantly (p<0.05) higher than in control brains, indicating the induction of astrogliosis as confirmed by immunostaining of brain sections. The detection of anti-NFs, as indicative of neuronal insult, was consistent with loss of hippocampal neurons in CA3 and CA1. Our results suggest that the detection of autoantibodies to neurotypic and gliotypic proteins may be used as peripheral biomarkers to reveal evidence of nervous system neurotoxicity.
authors.affiliation: Neurotoxicology Laboratory, Division of Health Professions and Natural Sciences, Mercy College, 555 Broadway, Dobbs Ferry, NY 10522, USA. helfawal@mercy.edu
authors.forename: Hassan A N
authors.initials: HA
authors.lastname: El-Fawal
authors.forename: James P
authors.initials: JP
authors.lastname: O'Callaghan
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005904:Glial Fibrillary Acidic Protein / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008297:Male; D004676:Myelin Basic Protein / Q000276:immunology; D009419:Nerve Tissue Proteins / Q000276:immunology*; D016900:Neurofilament Proteins / Q000276:immunology; D051381:Rats; D020318:Rats, Long-Evans; D013997:Time Factors; D014298:Trimethyltin Compounds / Q000494:pharmacology*
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D014298:Trimethyltin Compounds; C046488:trimethyltin