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ToxSci Advance Access originally published online on February 14, 2007
Toxicological Sciences 2007 97(1):181-188; doi:10.1093/toxsci/kfm017
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Long- and Short-Term Changes in the Neuroimmune-Endocrine Parameters following Inhalation Exposures of F344 Rats to Low-Dose Sarin

Juan Carlos Peña-Philippides, Seddigheh Razani-Boroujerdi, Shashi P. Singh, Raymond J. Langley, Neerad C. Mishra, Rogene F. Henderson and Mohan L. Sopori1

Immunology Division, Lovelace Respiratory Research Institute, 2425 Ridgecrest Dr SE, Albuquerque, New Mexico 87108

1 To whom correspondence should be addressed. Fax: (505) 348-4986. E-mail: msopori{at}lrri.org.

Received February 9, 2007; accepted February 12, 2007


  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 NF{kappa}B 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.

Key Words: organophosphates; sarin; neuroimmune modulation; glucocorticoids; hypothalamus-pituitary-adrenal (HPA) axis.


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