The detrimental effects of organophosphates (OPs) on human health are thought to be of systemic, i.e., irreversible inhibition of acetylcholinesterase (AChE) at nerve synapses. However, several studies have shown that AChE inhibition alone cannot explain all the toxicological manifestations in prolonged exposure to OPs. The present study aimed to assess the status of antioxidants malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) (reduced), catalase, and ferric reducing antioxidant power (FRAP) in chronic OP-exposed groups from Cameroon and Pakistan. Molecular analysis of genetic polymorphisms (SNPs) of glutathione transferases (GSTM1, GSTP1, GSTT1), catalase gene (CAT, rs7943316), sirtuin 1 gene (SIRT1, rs10823108), acetylcholinesterase gene (ACHE, rs2571598), and butyrylcholinesterase gene (BCHE, rs3495) were screened in the OP-exposed individuals to find the possible causative association with oxidative stress and toxicity. Cholinesterase and antioxidant activities were measured by colorimetric methods using a spectrophotometer. Salting-out method was employed for DNA extraction from blood followed by restriction fragment length polymorphism (RFLP) for molecular analysis. Cholinergic enzymes were significantly decreased in OP-exposed groups. Catalase and SOD were decreased and MDA and FRAP were increased in OP-exposed groups compared to unexposed groups in both groups. GSH was decreased only in Pakistani OPs-exposed group. Molecular analysis of ACHE, BCHE, Catalase, GSTP1, and GSTM1 SNPs revealed a tentative association with their phenotypic expression that is level of antioxidant and cholinergic enzymes. The study concludes that chronic OPs exposure induces oxidative stress which is associated with the related SNP polymorphism. The toxicogenetics of understudied SNPs were examined for the first time to our understanding. The findings may lead to a newer area of investigation on OPs induced health issues and toxicogenetics.

• Klíčová slova
• SNPs, antioxidants, cholinergic enzymes, organophosphates, toxicogenetics,
• MeSH
• acetylcholinesterasa genetika   MeSH
• butyrylcholinesterasa genetika   MeSH
• dospělí MeSH
• glutathion-S-transferasa fí genetika   MeSH
• glutathion MeSH
• glutathiontransferasa genetika   MeSH
• GPI-vázané proteiny genetika   MeSH
• interakce genů a prostředí * MeSH
• jednonukleotidový polymorfismus * MeSH
• katalasa genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• malondialdehyd MeSH
• mladiství MeSH
• mladý dospělý MeSH
• organofosforové sloučeniny škodlivé účinky   MeSH
• oxidační stres genetika   MeSH
• sirtuin 1 genetika   MeSH
• vystavení vlivu životního prostředí škodlivé účinky   analýza   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Kamerun MeSH
• Pákistán MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• ACHE protein, human MeSH Prohlížeč
• BCHE protein, human MeSH Prohlížeč
• butyrylcholinesterasa MeSH
• glutathion-S-transferasa fí MeSH
• glutathion MeSH
• glutathione S-transferase M1 MeSH Prohlížeč
• glutathione S-transferase T1 MeSH Prohlížeč
• glutathiontransferasa MeSH
• GPI-vázané proteiny MeSH
• GSTP1 protein, human MeSH Prohlížeč
• katalasa MeSH
• malondialdehyd MeSH
• organofosforové sloučeniny MeSH
• SIRT1 protein, human MeSH Prohlížeč
• sirtuin 1 MeSH

Quantitative genomic mapping of DNA damage may provide insights into the underlying mechanisms of damage and repair. Sequencing based approaches are bound to the limitations of PCR amplification bias and read length which hamper both the accurate quantitation of damage events and the ability to map them to structurally complex genomic regions. Optical Genome mapping in arrays of parallel nanochannels allows physical extension and genetic profiling of millions of long genomic DNA fragments, and has matured to clinical utility for characterization of complex structural aberrations in cancer genomes. Here we present a new mapping modality, Repair-Assisted Damage Detection - Optical Genome Mapping (RADD-OGM), a method for single-molecule level mapping of DNA damage on a genome-wide scale. Leveraging ultra-long reads to assemble the complex structure of a sarcoma cell-line genome, we mapped the genomic distribution of oxidative DNA damage, identifying regions more susceptible to DNA oxidation. We also investigated DNA repair by allowing cells to repair chemically induced DNA damage, pinpointing locations of concentrated repair activity, and highlighting variations in repair efficiency. Our results showcase the potential of the method for toxicogenomic studies, mapping the effect of DNA damaging agents such as drugs and radiation, as well as following specific DNA repair pathways by selective induction of DNA damage. The facile integration with optical genome mapping enables performing such analyses even in highly rearranged genomes such as those common in many cancers, a challenging task for sequencing-based approaches.

• Klíčová slova
• CNV, Cancer genomes, Cytogenetics, DNA damage, DNA repair, Long-reads, Nanochannels, OGM, Osteosarcoma, Oxidative damage, RADD, S.V., Single molecule, Toxicogenomics,
• MeSH
• bromičnany toxicita   MeSH
• lidé MeSH
• mapování chromozomů * přístrojové vybavení   metody   MeSH
• mikrofluidní analytické techniky * přístrojové vybavení   metody   MeSH
• nádorové buněčné linie MeSH
• nanotechnologie * přístrojové vybavení   metody   MeSH
• oprava DNA genetika   MeSH
• oxidační stres účinky léků   genetika   MeSH
• poškození DNA * genetika   MeSH
• regulace genové exprese MeSH
• stanovení celkové genové exprese MeSH
• toxikogenetika * přístrojové vybavení   metody   MeSH
• variabilita počtu kopií segmentů DNA MeSH
• zobrazení jednotlivé molekuly * přístrojové vybavení   metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• bromičnany MeSH
• potassium bromate MeSH Prohlížeč

BACKGROUND AND OBJECTIVES: Organophosphate (OPs) anticholinesterases are one of the main groups of pesticides used in agriculture. Harmful effects of OPs on health have been attributed primarily for irreversible inhibition of acetylcholinesterase (AChE) at nerve synapse. However, studies have shown that inhibition of AChE alone cannot explain all the maladies encountered in prolonged exposure to OPs. Predisposition to population heterogeneity and irregularities in various biochemicals like paraoxonases and inflammatory biochemicals are the possible affects of OPs long term exposure that may lead to sequels of diseases and are less addressed in literature. The study was aimed to assess the cholinergic enzymes (AChE and BChE), PON1, and inflammatory markers (IL1β, IL6, TNFα, CRP, Apo AI, Apo B) and determine the toxicogenetics association of PON1 gene (rs 662 and rs 85456) to chronically OPs exposed groups from Pakistan and Cameroon. MATERIALS AND METHODS: AChE, BChE and PON1 were measured by colorimetric method using spectrophotometry. Inflammatory markers were determined by Elisa assay. PCR-restriction fragment length polymorphism (PCR-RFLP) using salting out method was employed for SNP genotyping. RESULTS: The results revealed the significant (p ≤ 0.05) inhibition of cholinergic enzymes PON 1 was found to be 6.91 ng/mL±1.03 and 2.84 ng/mL±1.40 (mean ± SD) in Pakistan and Cameroon groups respectively. IL6, TNFα, CRP were increased and Apo AI was less while Apo B was increased in OP exposed groups in both population groups. SNPs analysis of PON1 showed significant differences in allelic and genotype frequencies of OPs exposed and non-exposed groups. CONCLUSIONS: PON1 was noticeably less in Cameroonian than Pakistani, albeit both groups have significant decrease in PON1 actity. In addition, the study concludes that OPs induce low grade inflammation, an aetiology of many diseases. Selected PON1 SNPs analysis showed a significant toxicogenetics association with OPs exposure marker enzymes. The results of this study may help in regulation of usage of OPs anticholinesterases in different populations. The study will further open new avenues in toxicogenetic and exploration of SNPs based strategies on organophosphate intoxication.

• Klíčová slova
• Apolipoprotein, Cholinergic enzymes, Cytokines, Organophosphates, PON1,toxicogenetic,
• MeSH
• acetylcholinesterasa genetika   MeSH
• aryldialkylfosfatasa genetika   MeSH
• lidé MeSH
• organofosfáty MeSH
• organofosforové sloučeniny * MeSH
• pesticidy * toxicita   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Pákistán MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• aryldialkylfosfatasa MeSH
• organofosfáty MeSH
• organofosforové sloučeniny * MeSH
• pesticidy * MeSH
• PON1 protein, human MeSH Prohlížeč