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Gene Expression Studies Reveal That DNA Damage, Vascular Perturbation, and Inflammation Contribute to the Pathogenesis of Carbonyl Sulfide Neurotoxicity

¹ Charles River Laboratories, Pathology Associates, Durham, NC 27703, USA
² Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC 27709, USA
³ Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC 27709, USA
⁴ Neuroscience Associates, Knoxville, TN 37934, USA

Correspondence: Robert C. Sills, MD-B3-06, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709, USA; e-mail:sills{at}niehs.nih.gov.

Carbonyl sulfide (COS) is an odorless gas that produces highly reproducible lesions in the central nervous system. In the present study, the time course for the development of the neurotoxicological lesions was defined and the gene expression changes occurring in the posterior colliculus upon exposure to COS were characterized. Fischer 344 rats were exposed to 0 or 500 ppm COS for one, two, three, four, five, eight, or ten days, six hours per day. On days 1 and 2, no morphological changes were detected; on day 3, 10/10 (100%) rats had necrosis in the posterior colliculi; and on day 4 and later, necrosis was observed in numerous areas of the brain. Important gene expression changes occurring in the posterior colliculi after one or two days of COS exposure that were predictive of the subsequent morphological findings included up-regulation of genes associated with DNA damage and G1/S checkpoint regulation (KLF4, BTG2, GADD45g), apoptosis (TGM2, GADD45g, RIPK3), and vascular mediators (ADAMTS, CTGF, CYR61, VEGFC). Proinflammatory mediators (CCL2, CEBPD) were up-regulated prior to increases in expression of the astrocytic marker GFAP and macrophage marker CSF2rb1. These gene expression findings were predictive of later CNS lesions caused by COS exposure and serve as a model for future investigations into the mechanisms of disease in the central nervous system.

Key Words: gene expression • carbonyl sulfide • posterior colliculus • brain • neurotoxicity • neuropathology • transcriptome

Abbreviations: BAER, brain stem auditory evoked responses; • CEBPD, CCAAT/enhancer binding protein delta; • COS, carbonyl sulfide; • GFAP, glial fibrillary acidic protein; • RT-PCR, reverse transcriptase polymerase chain reaction.

This version was published on June 1, 2009

Toxicologic Pathology, Vol. 37, No. 4, 502-511 (2009)
DOI: 10.1177/0192623309335631


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