Gene expression studies reveal that DNA damage, vascular perturbation, and inflammation contribute to the pathogenesis of carbonyl sulfide neurotoxicity.
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.
Morrison
James P
JP
Charles River Laboratories, Pathology Associates, Durham, NC 27703, USA.
Ton
Thai-Vu
TV
Collins
Jennifer B
JB
Switzer
Robert C
RC
Little
Peter B
PB
Morgan
Daniel L
DL
Sills
Robert C
RC
D000280:Administration, Inhalation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001927:Brain Diseases / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects*; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D008297:Male; D009336:Necrosis; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013461:Sulfur Oxides / Q000008:administration & dosage / Q000633:toxicity*
D005904:Glial Fibrillary Acidic Protein; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D013461:Sulfur Oxides; C000717609:Tgm2 protein, rat; C010063:carbonyl sulfide; D000091345:Protein Glutamine gamma Glutamyltransferase 2