title: Long- and short-term changes in the neuroimmune-endocrine parameters following inhalation exposures of F344 rats to low-dose sarin.
abstract: Inhalation of subclinical doses of sarin suppresses the antibody-forming cell (AFC) response, T-cell mitogenesis, and serum corticosterone (CORT) levels, and high doses of sarin cause lung inflammation. However, the duration of these changes is not known. In these studies, rats were exposed to a subclinical dose of sarin (0.4 mg/m3/h/day) for 1 or 5 days, and immune and inflammatory parameters were assayed up to 8 weeks before sarin exposure. Our results showed that the effects of a 5-day sarin exposure on the AFC response and T-cell receptor (TCR)-mediated Ca2+ response disappeared within 2-4 weeks after sarin exposure, whereas the CORT and adrenocorticotropin hormone (ACTH) levels remained significantly decreased. Pretreatment of rats with chlorisondamine attenuated the effects of sarin on the AFC and the TCR-mediated Ca2+ response, implicating the autonomic nervous system (ANS) in the sarin-induced changes in T-cell function. Moreover, exposure to a single or five repeated subclinical doses of sarin upregulated the mRNA expression of proinflammatory cytokines in the lung, which is associated with the activation of NFkappaB in bronchoalveolar lavage cells. These effects were lost within 2 weeks of sarin inhalation. Our results suggest that while sarin-induced changes in T cells and cytokine gene expression were short lived, suppression of CORT and ACTH levels were relatively long lived and might represent biomarkers of sarin exposure. Moreover, while the effects of sarin on T-cell function were regulated by the ANS, the decreased CORT levels by sarin might result from its effects on the hypothalamus-pituitary-adrenal axis.
authors.affiliation: Immunology Division, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Peña-Philippides
authors.forename: Seddigheh
authors.initials: S
authors.lastname: Razani-Boroujerdi
authors.forename: Shashi P
authors.initials: SP
authors.lastname: Singh
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Langley
authors.forename: Neerad C
authors.initials: NC
authors.lastname: Mishra
authors.forename: Rogene F
authors.initials: RF
authors.lastname: Henderson
authors.forename: Mohan L
authors.initials: ML
authors.lastname: Sopori
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects* / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D002118:Calcium / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002714:Chlorisondamine / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005730:Ganglionic Blockers / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D015213:Neuroimmunomodulation / Q000187:drug effects*; D009490:Neurosecretory Systems / Q000187:drug effects* / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000378:metabolism; D012524:Sarin / Q000008:administration & dosage / Q000633:toxicity*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D015415:Biomarkers; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D016207:Cytokines; D005730:Ganglionic Blockers; D016328:NF-kappa B; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D000324:Adrenocorticotropic Hormone; D012524:Sarin; D002714:Chlorisondamine; D002118:Calcium; D003345:Corticosterone