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      Monocrotophos Induced Apoptosis in PC12 Cells: Role of Xenobiotic Metabolizing Cytochrome P450s

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          Abstract

          Monocrotophos (MCP) is a widely used organophosphate (OP) pesticide. We studied apoptotic changes and their correlation with expression of selected cytochrome P450s (CYPs) in PC12 cells exposed to MCP. A significant induction in reactive oxygen species (ROS) and decrease in glutathione (GSH) levels were observed in cells exposed to MCP. Following the exposure of PC12 cells to MCP (10 −5 M), the levels of protein and mRNA expressions of caspase-3/9, Bax, Bcl 2, P 53, P 21, GSTP1-1 were significantly upregulated, whereas the levels of Bclw, Mcl1 were downregulated. A significant induction in the expression of CYP1A1/1A2, 2B1/2B2, 2E1 was also observed in PC12 cells exposed to MCP (10 −5 M), whereas induction of CYPs was insignificant in cells exposed to 10 −6 M concentration of MCP. We believe that this is the first report showing altered expressions of selected CYPs in MCP-induced apoptosis in PC12 cells. These apoptotic changes were mitochondria mediated and regulated by caspase cascade. Our data confirm the involvement of specific CYPs in MCP-induced apoptosis in PC12 cells and also identifies possible cellular and molecular mechanisms of organophosphate pesticide-induced apoptosis in neuronal cells.

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          The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis.

          Daniel Nebert, Timothy Dalton (2006)
          Some cytochrome P450 (CYP) heme-thiolate enzymes participate in the detoxication and, paradoxically, the formation of reactive intermediates of thousands of chemicals that can damage DNA, as well as lipids and proteins. CYP expression can also affect the production of molecules derived from arachidonic acid, and alters various downstream signal-transduction pathways. Such changes can be precursors to malignancy. Recent studies in mice have changed our perceptions about the function of CYP1 enzymes. We suggest a two-tiered system to predict an overall inter-individual risk of tumorigenesis based on DNA variants in certain 'early defence' CYP genes, combined with polymorphisms in various downstream target genes.
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            Current issues in organophosphate toxicology.

            Pietra L. Costa (2006)
            Organophosphates (OPs) are one of the main classes of insecticides, in use since the mid 1940s. OPs can exert significant adverse effects in non-target species including humans. Because of the phosphorylation of acetylcholinesterase, they exert primarily a cholinergic toxicity, however, some can also cause a delayed polyneuropathy. Currently debated and investigated issues in the toxicology of OPs are presented in this review. These include: 1) possible long-term effects of chronic low-level exposures; 2) genetic susceptibility to OP toxicity; 3) developmental toxicity and neurotoxicity; 4) common mechanism of action; 5) mechanisms of delayed neurotoxicity; and 6) possible additional OP targets. Continuing and recent debates, and molecular advances in these areas, and their contributions to our understanding of the toxicology of OPs are discussed.
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              Comparative developmental neurotoxicity of organophosphates in vivo: transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems.

              Frederic Seidler, Theodore A. Slotkin (2007)
              Organophosphates affect mammalian brain development through a variety of mechanisms beyond their shared property of cholinesterase inhibition. We used microarrays to characterize similarities and differences in transcriptional responses to chlorpyrifos and diazinon, assessing defined gene groupings for the pathways known to be associated with the mechanisms and/or outcomes of chlorpyrifos-induced developmental neurotoxicity. We exposed neonatal rats to daily doses of chlorpyrifos (1mg/kg) or diazinon (1 or 2mg/kg) on postnatal days 1-4 and evaluated gene expression profiles in brainstem and forebrain on day 5; these doses produce little or no cholinesterase inhibition. We evaluated pathways for general neural cell development, cell signaling, cytotoxicity and neurotransmitter systems, and identified significant differences for >60% of 252 genes. Chlorpyrifos elicited major transcriptional changes in genes involved in neural cell growth, development of glia and myelin, transcriptional factors involved in neural cell differentiation, cAMP-related cell signaling, apoptosis, oxidative stress, excitotoxicity, and development of neurotransmitter synthesis, storage and receptors for acetylcholine, serotonin, norepinephrine and dopamine. Diazinon had similar effects on many of the same processes but also showed major differences from chlorpyrifos. Our results buttress the idea that different organophosphates target multiple pathways involved in neural cell development but also that they deviate in key aspects that may contribute to disparate neurodevelopmental outcomes. Equally important, these pathways are compromised at exposures that are unrelated to biologically significant cholinesterase inhibition and its associated signs of systemic toxicity. The approach used here demonstrates how planned comparisons with microarrays can be used to screen for developmental neurotoxicity.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2011
                Publication date (Electronic): 21 March 2011
                Volume: 6
                Issue: 3
                Electronic Location Identifier: e17757
                Affiliations
                [1 ]Indian Institute of Toxicology Research, Lucknow, India
                [2 ]Council of Scientific and Industrial Research, New Delhi, India
                [3 ]Department of Biotechnology, Jamia Hamdard University, New Delhi, India
                Johns Hopkins School of Medicine, United States of America
                Author notes

                Conceived and designed the experiments: MPK ABP. Performed the experiments: MPK AKS VK VKT RKS MA SY ABP. Analyzed the data: MPK ABP. Contributed reagents/materials/analysis tools: MPK AKS VK VKT RKS SY VKK SKJ ABP. Wrote the paper: MPK ABP.

                Article
                Publisher ID: PONE-D-10-05557
                DOI: 10.1371/journal.pone.0017757
                PMC ID: 3061860
                PubMed ID: 21445290
                SO-VID: 86897245-f58d-4534-8584-47e78e751b39
                Copyright © Kashyap et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 23 November 2010
                Date accepted : 9 February 2011
                Page count
                Pages: 11
                Categories
                Subject: Research Article
                Subject: Agriculture
                Subject: Agrochemicals
                Subject: Pesticides
                Subject: Biology
                Subject: Molecular Cell Biology
                Subject: Cell Death
                Subject: Toxicology
                Subject: Neurotoxicology
                Subject: Medicine
                Subject: Public Health
                Subject: Environmental Health
                Subject: Toxicology
                Subject: Neurotoxicology

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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