Dimethyl sulfate uptake and methylation of DNA in rat respiratory tissues following acute inhalation.
Adult male CrlCD:BR rats were exposed nose-only to several concentrations of dimethyl sulfate (DMS) vapors to determine the relationships between vapor uptake and DNA methylation. Following DMS exposure, nasal respiratory and olfactory mucosa and lung tissue were removed and DNA was isolated for the analysis of methylated purines. DMS vapor uptake was complex and related to exposure concentration; clearance appeared to increase with increasing DMS concentrations between 0.5 and 8 ppm. Plethysmorgraphic measurements correlated with the time-dependent disappearance of dimethyl sulfate from a closed exposure apparatus. Above an initial DMS concentration of 8 ppm, sensory irritancy apparently altered normal respiratory parameters, clearance, and regional DNA methylation. DMS-dependent N7-methylguanine formation in DNA isolated from nasal respiratory mucosa was detectable 30 min following a 20-min exposure to an initial DMS concentration of 1 ppm. DMS-dependent methylation of DNA, as evidenced by N7-methylguanine and N3-methyladenine formation, showed concentration-response relationships in all tissues examined and was correlated with vapor uptake. DNA adduct formation showed regional differences characteristic of the absorption of a water-soluble vapor; methylation was greatest in DNA isolated from respiratory mucosa, less in olfactory, and little in lung. Repair of N7-methylguanine did not appear to be significantly different between nasal respiratory and olfactory tissues. These experiments demonstrate that DMS is a potent methylating agent of nasal mucosa in vivo.
Mathison
B H
BH
Haskell Laboratory for Toxicology and Industrial Medicine, E. I. du Pont de Nemours and Company, Newark, Delaware 19714, USA.
Taylor
M L
ML
Bogdanffy
M S
MS
D000280:Administration, Inhalation; D000818:Animals; D001273:Atmosphere Exposure Chambers; D004247:DNA / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D006147:Guanine / Q000031:analogs & derivatives / Q000096:biosynthesis; D008168:Lung / Q000378:metabolism; D008297:Male; D008745:Methylation; D009079:Mucociliary Clearance; D009092:Mucous Membrane / Q000378:metabolism; D051381:Rats; D012119:Respiration / Q000187:drug effects; D012137:Respiratory System / Q000187:drug effects* / Q000378:metabolism*; D013463:Sulfuric Acid Esters / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D013997:Time Factors
D018736:DNA Adducts; D013463:Sulfuric Acid Esters; D006147:Guanine; D004247:DNA; C007482:dimethyl sulfate