Gene expression studies reveal that DNA damage, vascular perturbation, and inflammation contribute to the pathogenesis of carbonyl sulfide neurotoxicity.

Abstract:

: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.

journal_name

Toxicol Pathol

journal_title

Toxicologic pathology

authors

Morrison JP,Ton TV,Collins JB,Switzer RC,Little PB,Morgan DL,Sills RC

doi

10.1177/0192623309335631

subject

Has Abstract

pub_date

2009-06-01 00:00:00

pages

502-11

issue

4

eissn

0192-6233

issn

1533-1601

pii

0192623309335631

journal_volume

37

pub_type

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