title: Distribution of DNA adducts and corresponding tissue damage of Sprague-Dawley rats with percutaneous exposure to sulfur mustard.
abstract: Sulfur mustard (SM) is a highly reactive alkylation vesicant and cytotoxic agent that has been recognized as an animal and human carcinogen. Although the exact mechanism of toxicology is vague, DNA alkylation seems to be responsible for the triggering of apoptosis. In this study, after male adult Sprague-Dawley rats were cutaneous exposed to a low concentration of SM at parts-per-million levels, their lungs, livers, pancreases, spleens, marrow, and brains were collected at 11 different time points and analyzed. N7-[2-[(2-hydroxyethyl)thio]-ethyl]guanine (N7-HETEG), N3-[2-[(2-hydroxyethyl)thio]-ethyl]adenine (N3-HETEA), and bis[2-(guanin-7-yl)ethyl]sulfide (Bis-G) as the biomarkers for DNA damage were measured in the vital tissues by isotope dilution ultraperformance liquid chromatography tandem mass spectrometry (ID-UPLC-MS/MS). At the same time, general variations and pathological changes were monitored and detected to evaluate the tissue damage. Time- and dose-dependent data showed that SM had strong permeability and reactivity and that three SM-DNA adducts were detected in all investigated tissues only after 10 min after exposure. Obvious dose-dependency was observed except in the brain and pancreas. Most times to peak (tmax) of all three adducts were less than 3 h, while half-lifetimes (t1/2) were less than 24 h. We also suggested that the lipophilic SM can easily pass through the blood-brain barrier and can be stored in the fatty organs. To the best of our knowledge, the abundant adducts in marrow were found and reported for the first time. The surveillance of N7-HETEG in vivo, which was the most abundant adduct, may be the most efficient indicator to validate SM exposure even without any symptoms. Bis-G can be regarded as a biomarker of effect, which is directly related to the extent of damage. The most abundant Bis-G was found in the most sensitive tissues, marrow, spleen, and lung, which is in good accordance with histopathologic results. General variations and pathological changes were evaluated as well. After cutaneous exposure to SM, the body weights of rats heavily decreased in the first 4 days and were inversely proportional to the applied doses, and then recovered at the last experimental day except for those of the rats at the highest dosing level, in which the relative weights of rat spleens were obviously lost. Moreover, we found remarkable histological changes of the lung and skin, such as encephalemia, at the very beginning of the sampling procedure, and plentiful mononuclear cells in marrow appeared 6 h after exposure. The micronucleus test of marrow cells showed that the micronucleus rate had a positively dose-dependent effect.
authors: State Key Laboratory for Toxicology and Medical Countermeasures, and Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences , No. 27 Taiping Road, Haidian District, 100850, Beijing, China.
authors: Lijun
authors: L
authors: Yue
authors: Yajiao
authors: Y
authors: Zhang
authors: Jia
authors: J
authors: Chen
authors: Zengming
authors: Z
authors: Zhao
authors: Qin
authors: Q
authors: Liu
authors: Ruiqin
authors: R
authors: Wu
authors: Lei
authors: L
authors: Guo
authors: Jun
authors: J
authors: He
authors: Jun
authors: J
authors: Zhao
authors: Jianwei
authors: J
authors: Xie
authors: Shuangqing
authors: S
authors: Peng
mesh_terms: D000279:Administration, Cutaneous; D000477:Alkylating Agents / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D018736:DNA Adducts / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D015162:Micronucleus Tests; D009151:Mustard Gas / Q000008:administration & dosage / Q000633:toxicity*; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D000477:Alkylating Agents; D002273:Carcinogens; D018736:DNA Adducts; D009151:Mustard Gas