Sulfur mustard (SM), a chemical warfare agent, can form adducts with DNA, RNA, and proteins. Reactions with DNA lead to the formation of both DNA monoadducts and interstrand cross-links, resulting in DNA damage, and is an important component of SM toxicity. Our previous in vivo studies indicated that dividing cells such as hematopoietic stem cells and intestinal villi stem cells seemed to have increased sensitivity to SM. Therefore, to compare the sensitivity of somatic and stem cells to SM and to investigate the mechanism of SM cytotoxicity, we isolated human foreskin fibroblasts, reprogrammed them into pluripotent stem cells, and then compared the DNA damage repair pathways involved upon SM treatment. Our results indicated that proliferating stem cells were more sensitive to SM-induced DNA damage, and the damage mainly comprised single-stranded breaks. Furthermore, the pathways involved in DNA repair in stem cells and somatic cells were different.

Sulfur mustard (SM) exposure, whose symptoms are similar to radiation exposure, can lead to acute injury. Because mesenchymal stromal cells (MSCs) have been used to experimentally and clinically treat acute radiation syndrome, in this study, MSCs were intravenously injected into rats after percutaneous SM exposure. Then, we examined sternum and spleen samples by histopathological and immunohistochemical methods to observe pathological changes. Furthermore, blood samples were taken to test the white blood cell (WBC) count, blood platelet count (BPC), red blood cell count, and the levels of cytokines in the serum. The number of bone marrow karyocytes and the WBC in the MSC + SM group were higher than those in the SM group, and the levels of granulocyte colony-stimulating factor, granulocyte-macrophage colony stimulating factor, monocyte chemoattractant protein-1, interleukin (IL)-1α, IL-5, and interferon-γ in the MSC + SM group remained high at different time points after SM exposure. In addition, the BPC, the level of erythropoietin and the relative weight of the spleen in the MSC + SM group were significantly higher than those in the SM group. Meanwhile, spleens in the MSC + SM group were more hyperplastic and hematopoietic, and had fewer apoptotic cells than in the SM group. Furthermore, rat body weight and locomotion ability in the MSC + SM group were higher than in the SM group. This evidence supports the potential ability of MSCs in immunoregulation and functional improvements to the hemopoietic microenvironment. Intravenous injection of MSCs exerted significant therapeutic effects in rats with percutaneous exposure to SM.

Growing black carbon (BC) emission has become one of the major urgent environmental issues facing human beings. Usually, BC or BC-containing carbon nanoparticles (CNPs) were recognized as non-directly toxic components of atmospheric particulate matter. However, epidemiology studies have provided much evidence of the associations of exposure of particulate-containing carbon particles with cardiovascular diseases. There are still no related studies to support the epidemiological conclusions. Hence, in this article we exposed adult zebrafish to CNPs for 60 days, and then explored the heart location and potential adverse effects on cardiac tissues of these nanosized carbon particles. Our results first showed direct visualization of cardiac endothelial uptake and heart deposition of CNPs in zebrafish. In addition, CNPs caused significant ultrastructural alterations in myocardial tissue and induced the expression of inflammatory cytokines in a dose-dependent manner, resulting in sub-endocardial inflammation and cell apoptosis. Moreover, our data demonstrated the perturbations caused by CNPs on DNA methylation, suggesting that DNA methylome remodeling might play a critical role in CNP-induced cardiotoxicity in zebrafish heart. Therefore, this study not only proved a laboratory link between CNP exposure and cardiotoxicity in vivo, but also indicated a possible toxicity mechanism involved.

Concerns regarding the adverse effects of long-term exposure to low levels of rare earth elements (REEs) from foods on human health have arisen in recent years. Nevertheless, no official acceptable daily intake (ADI) has yet been proposed for either total REEs or individual REE. In accordance with the Organization for Economic Co-operation and Development (OECD) testing guideline, the present study was undertaken to evaluate the subchronic toxicity of yttrium, a representative heavy REE with higher contaminated level in foods in China, to achieve a no observed adverse effect level (NOAEL) which is a critical basis for the establishment of an ADI. Yttrium nitrate was orally administered to rats at doses of 0, 10, 30 and 90 mg/kg/day for 90 days followed by a recovery period of 4 weeks. The following toxicity indices were measured: mortality, clinical signs, daily food consumption and weekly body weight; urinalysis, hematology, blood coagulation, clinical biochemistry and histopathology at the end of administration and recovery periods. No toxicologically significant changes were found in any yttrium-treated group as compared to the concurrent control group. Under the present experimental condition, the NOAEL in rats was thus set at 90 mg/kg for yttrium nitrate, i.e. 29.1 mg/kg for yttrium.

Long-term exposure to fine particulate matter (PM2.5) has been reported to be closely associated with the increased lung cancer risk in populations, but the mechanisms underlying PM-associated carcinogenesis are not yet clear. Previous studies have indicated that aberrant epigenetic alterations, such as genome-wide DNA hypomethylation and gene-specific DNA hypermethylation contribute to lung carcinogenesis. And silence or mutation of P53 tumor suppressor gene is the most prevalent oncogenic driver in lung cancer development. To explore the effects of PM2.5 on global and P53 promoter methylation changes and the mechanisms involved, we exposed human bronchial epithelial cells (BEAS-2B) to low concentrations of PM2.5 for 10 days. Our results indicated that PM2.5-induced global DNA hypomethylation was accompanied by reduced DNMT1 expression. PM2.5 also induced hypermethylation of P53 promoter and inhibited its expression by increasing DNMT3B protein level. Furthermore, ROS-induced activation of Akt was involved in PM2.5-induced increase in DNMT3B. In conclusion, our results strongly suggest that repeated exposure to PM2.5 induces epigenetic silencing of P53 through ROS-Akt-DNMT3B pathway-mediated promoter hypermethylation, which not only provides a possible explanation for PM-induced lung cancer, but also may help to identify specific interventions to prevent PM-induced lung carcinogenesis.

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 alkylarion 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-[(2hydrokyethypthio] -ethyl] guanine (N7-HETEG), N342-[(2hydroxyethypthio]-ethylladenine (N3-14ETEA), and bis[24guanin7-ypethyl]sulfide (Iii.S.,G) as the biornarkets for DNA damage were measured in the vital tissues by isotope dilution ultraperfoimance, 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 teactivity and that three $M-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 (t(max)) of all three adducts were less than 3 h, while half-lifetimes (t(1/2)) were less than 24 h. We also suggested that the lipophilit 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 N7HETEG 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 first4 days and were inversely proportional to the applied dose, 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 tat 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.

Sulfur mustard (SM) is a highly reactive alkylating vesicant and causes blisters upon contact with skin, eyes, and respiratory organs. It covalently links with DNAs by forming four mono- or cross-link adducts. In this article, the reference standards of SM-DNA adducts and deuterated analogues were first synthesized with simplified procedures containing only one or two steps and using less toxic chemical 2-(2-chloroethylthio)ethanol or nontoxic chemical thiodiglycol as starting materials. A sensitive and high-throughput simultaneous quantification method of N(7)-[2-[(2-hydroxyethyl)thio]-ethyl]guanine (N(7)-HETEG), O(6)-[2-[(2-hydroxyethyl)thio]-ethyl]guanine (O(6)-HETEG), N(3)-[2-[(2-hydroxyethyl)thio]-ethyl]adenine (N(3)-HETEA), and bis[2-(guanin-7-yl)ethyl]sulfide (Bis-G) in the Sprague-Dawley rat derma samples was developed by stable isotope dilution-ultrahigh performance liquid chromatography-tandem mass spectrometry (ID-UPLC-MS/MS) with the aim of revealing the real metabolic behaviors of four adducts. The method was validated, the limit of detection (S/N ratio greater than 10) was 0.01, 0.002, 0.04, and 0.11 fmol on column for N(7)-HETEG, O(6)-HETEG, Bis-G, and N(3)-HETEA, respectively, and the lower limit of quantification (S/N ratio greater than 20) was 0.04, 0.01, 0.12, and 0.33 fmol on column for N(7)-HETEG, O(6)-HETEG, Bis-G, and N(3)-HETEA, respectively. The accuracy of this method was determined to be 76% to 129% (n = 3), and both the interday (n = 6) and intraday (n = 7) precisions were less than 10%. The method was further applied for the quantifications of four adducts in the derma of adult male Sprague-Dawley rats exposed to SM ex vivo and in vivo, and all adducts had time- and dose-effect relationships. To the best of our knowledge, this is the first time that the real presented status of four DNA adducts was simultaneously revealed by the MS-based method, in which Bis-G showed much higher abundance than the result previously reported and N(3)-HETEA showed much less. It should be noted that since the interstrand cross-linked adduct is believed to stall DNA replication and finally induce a double-strand break, the higher abundance of Bis-G is a great indication of a more serious DNA lesion by SM alkylation.