Abstract
Sulfur mustard is a vesicant chemical warfare agent, which has been used during Iraq-Iran-war. Many veterans and civilians still suffer from long-term complications of sulfur mustard exposure, especially in their lung. Although the lung lesions of these patients are similar to Chronic Obstructive Pulmonary Disease (COPD), there are some differences due to different etiology and clinical care. Less is known on the molecular mechanism of sulfur mustard patients and specific treatment options. microRNAs are master regulators of many biological pathways and proofed to be stable surrogate markers in body fluids. Based on that microRNA expression for serum samples of sulfur mustard patients were examined, to establish specific microRNA patterns as a basis for diagnostic use and insight into affected molecular pathways. Patients were categorized based on their long-term complications into three groups and microRNA serum levels were measured. The differentially regulated microRNAs and their corresponding gene targets were identified. Cell cycle arrest, ageing and TGF-beta signaling pathways showed up to be the most deregulated pathways. The candidate microRNA miR-143-3p could be validated on all individual patients. In a ROC analysis miR-143-3p turned out to be a suitable diagnostic biomarker in the mild and severe categories of patients. Further microRNAs which might own a link to the biology of the sulfur mustard patients are miR-365a-3p, miR-200a-3p, miR-663a. miR-148a-3p, which showed up only in a validation study, might be linked to the airway complications of the sulfur mustard patients. All the other candidate microRNAs do not directly link to COPD phenotype or lung complications. In summary the microRNA screening study characterizes several molecular differences in-between the clinical categories of the sulfur mustard exposure groups and established some useful microRNA biomarkers. qPCR raw data is available via the Gene Expression Omnibus https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE110797.
Highlights
Sulfur mustard [bis (2-chloroethyl) sulfide] is a vesicant chemical warfare agent, which has been used during world war I (1914–1918) and in recent times during 8-year Iraq-Iran-war (1980–1988) [1]
Following RNA extraction and cDNA synthesis, quantitative PCR array of microRNAs was performed on serum samples
The results set between the mild and severe group of nine overlapping microRNAs points to. It seems that cell cycle arrest, TGF-beta signaling pathway, apoptosis and senescence are the main affected pathways in SMV patients (Fig 6)
Summary
Sulfur mustard [bis (2-chloroethyl) sulfide] is a vesicant chemical warfare agent, which has been used during world war I (1914–1918) and in recent times during 8-year Iraq-Iran-war (1980–1988) [1]. Sulfur mustard reacts with a lot of macromolecules in the human body. DNA and RNA in the cells are the obvious targets of sulfur mustard and this interaction is responsible for many clinical manifestations of sulfur mustard exposure [2, 3]. The guanine base of nucleotides is the preferential site of sulfur mustard action which can lead to mono- and bifunctional adducts [2]. These adducts are preferentially found at the N7 position of guanine but rarely at O6 position. Bifuntional sulfur mustard adducts including intra- or inter strand crosslinks occurred in nearly 17% of the sulfur mustard alkylations resulting in single or double strand DNA breaks [2]. In vitro and in vivo experiments showed that, beyond a certain amount of DNA alkylation, the direct consequences are apoptosis or necrosis [4]
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