ABC  Vol.3 No.5 , October 2013
Protein phosphorylation pathways disruption by pesticides
Phosphosites in the human proteome represent an excellent source of potential biomarkers of pesticide toxicity. In fact, experimental animal models as well as in vitro studies have revealed phosphorylation disruption associated to metabolic regulation, hormone signaling, neuronal function and differentiation, cell survival and death. Due to their estrogen-mimicking ability, pesticides are considered as prime etiological suspects of increasing tumor incidence. Evidences of alterations in the signal transduction pathways involved in the tumor progression stage of pesticides were also provided. Despite progress in understanding the effect of pesticides on the human phosphorproteome and their health outcomes, it remains a complex issue to be studied. By now, the potential impact of pesticides in epigenetic phosphorylation pathways remains poorly explored. In addition, studies involving pesticides mixtures effects are needed. This review updates and provides a comprehensive discussion on the molecular and biochemical events underlying protein phosphorylation pathway disruption caused by pesticides most frequently detected in human tissues and fluids, such as organochlorine pesticides and organophosphates. The link between epidemiological studies and experimental approaches is also considered. Future challenges, such as micro-array phosphoproteome studies to complement gene expression arrays to understand the mechanisms involved in pesticide toxicology are briefly discussed.

Cite this paper
Magnarelli, G. and Fonovich, T. (2013) Protein phosphorylation pathways disruption by pesticides. Advances in Biological Chemistry, 3, 460-474. doi: 10.4236/abc.2013.35050.
[1]   Mostafalou, S. and Abdollahi, M. (2013) Pesticides and human chronic diseases: Evidences, mechanisms, and perspectives. Toxicology and Applied Pharmacology, 268, 157-177.

[2]   Agrawi, A. and Sharma, B. (2010) Pesticides induced oxidative stress in mammalian systems. International Journal of Biological and Medical Research, 1, 90-104.

[3]   Cohn, B., Cirillo, P. and Christianson, R. (2010) Prenatal DDT exposure and testicular Cancer: A nested case-control study. Archives of Environmental and Occupational Health, 65, 127-134.

[4]   Bouvier, G., Blanchard, O., Momas, I. and Seta, N. (2006) Pesticide exposure of non-occupationally exposed subjects compared to some occupational exposure: A French pilot study. Science of the Total Environment, 366, 74-91.

[5]   Bouwman, H., van den Berg, H. and Kylin, H. (2011) DDT and malaria prevention: Addressing the paradox. Environmental Health Perspectives, 119, 744-747.

[6]   Engeler, E. (2009) UN: Treaty Expanded by 9 more Dangerous Chemicals, The Guardian.

[7]   Pathak, R., Mustafa, M.D., Ahmed, R., Tripathi, A., Guleria, K. and Banerjee, B.D. (2010) Association between recurrent Miscarriages and Organochlorine Pesticide Levels. Clinical Biochemistry, 43, 131-135.

[8]   Agrawal, A. and Sharma, B. (2010) Pesticide induced oxidative stress in mammalian system. A review. International Journal and Medical Research, 1, 90-104.

[9]   Gwinn, M.R., Whipkey, D.L., Tennant, L.B. and Weston, A. (2005) Differential gene expression in normal human mammary epithelial cells treated with malathion monitored by DNA microarrays. Environmental Health Perspectives, 113, 1046-1051.

[10]   Casida, J. and Quistad, G. (2004) Organophosphate Toxicology: Safety aspects of nonacetylcholinesterase seconddary targets. Chemical Research in Toxicology, 17, 983-992.

[11]   Sengupta, D., Wasim Aktar, M., Alam, S. and Chowdhury, A. (2010) Impact assessment and decontamination of pesticides from meat under different culinary processes. Earth and Environmental Science Environmental Monitoring and Assessment, 169, 37-43.

[12]   Eaton, D.L., Daroff, R.B., Autrup, H., Bridges, J., Buffler, P., Costa, L.G. and Spencer, P.S. (2008) Review of the toxicology of chlorpyrifos with an emphasis on human exposure and neurodevelopment. Critical Reviews in Toxicology, 38, 1-125.

[13]   Zhang, H. and Pelech, S. (2012) Using protein microarrays to study phosphorylation-mediated signal transduction. Seminars in Cell & Developmental Biology, 23, 872-882.

[14]   Roskoski, R., Jr. (2012) ERK1/2 MAP kinases: Structure, function, and regulation. Pharmacological Research, 66, 105-143.

[15]   Marino, M., Pellegrini, M., La Rosa, P. and Acconcia, F. (2012) Susceptibility of estrogen receptor rapid responses to xenoestrogens: physiological outcomes. Steroids, 77, 910-917.

[16]   Swedenborg, E., Ruegg, J., Makela, S. and Pongratz, I. (2009) Endocrine disruptive chemicals: Mechanisms of action and involvement in metabolic disorders. Journal of Molecular Endocrinology, 43, 1-10.

[17]   Fowler, P.A, Bellingham, M., Sinclair, K.D., Evans, N.P., Pocar, P., Fischer, B., Schaedlich, K., Schmidt, J.-S., Amezaga, M., R., Bhattacharya, S., Rhind, S.M. and O’Shaughnessy, P.J. (2012) Impact of endocrine-disrupting compounds (EDCs) on female reproductive health. Molecular and Cellular Endocrinology, 355, 231-239.

[18]   Rogan, W. and Chen, A. (2005) Health risks and benefits of bis(4-chlorophenyl)-1,1,1-trichloroethene (DDT). Lancet, 366, 763-773.

[19]   Tilghman, S.L., Nierth-Simpsonb, E. N.,Wallacec, R., Burowd, M.E. and Mc Lachlane, J.A. (2010) Environmental hormones: Multiple pathways for response may lead to multiple disease outcomes. Steroids, 75, 520-523.

[20]   Jeng, Y. and Watson C.-S. (2011) Combinations of physiologic estrogens with xenoestrogens alter ERK phosphorylation profiles in rat pituitary cells. Environmental Health Perspectives, 119, 104-112.

[21]   Junttila, M.R., Li, S.-P. and Westermarck, J. (2008) Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. The FASEB Journal, 22, 4954-4965.

[22]   Bulayeva, N. N. and Watson, C. S. (2004) Xenoestrogeninduced ERK-1 and ERK-2 activation via multiple membrane-initiated signaling pathways. Environmental Health Perspectives, 112, 1481-1487.

[23]   Li, X., Zhang, S., and Safe, S. (2006) Activation of kinase pathways in MCF-7cells by 17beta-estradiol and structurally diverse estrogenic compounds. The Journal of Steroid Biochemistry and Molecular Biology, 98, 122-132.

[24]   Liu, J., Zhao, M., Zhuang, S., Yang, Y., Yang, Y., et al. (2012) Low concentrations of o,p’-DDT inhibit gene expression and prostaglandin synthesis by estrogen receptor-independent mechanism in rat ovarian cells. PLoS ONE, 7, e49916.

[25]   Korrick, S.A., Chen, C., Damokosh, A.W., Ni, J., Liu, X., Sung, I.C., Altshul, L., Ryan L. and Xu, X. (2001) Association of DDT with spontaneous abortion: A case-control study. Annals of Epidemiology, 11, 491-496.

[26]   Longnecker, M.,P., Klebanoff, M.A., Zhoo, H. and Bruck, J.W. (2001) Association between maternal serum concentration of the DDT metabolite DDE and preterm and small for gestational age babies at birth. Lancet, 358, 110-114.

[27]   Delidaki, M, Gu, M., Hein, A., Vatish, M. and Grammatopoulos, D.K. (2011) Interplay of cAMP and MAPK pathways in hCG secretion and fusogenic gene expression in a trophoblast cell line. Molecular and Cellular Endocrinology, 332, 213-320.

[28]   Gomez-Concha, C., Flores-Herrera, O., Olvera-Sanchez, S., Espinosa-Garcia, M.T. and Martinez, F. (2011) Progesterone synthesis by human placental mitochondria is sensitive to PKA inhibition by H89. International Journal of Biochemistry and Cell Biology, 43, 1402-1411.

[29]   Magnarelli, G., Souza, M.S and P. de D’ Angelo and A.M. (2009) Heptachlor and op’DDT effects on protein kinase activities associated with human placenta particulated fractions. Biochemical and Molecular Toxicology, 23, 185-192.

[30]   Maldonado-Mercado, M., Espinosa-Garc’ia, M.T., Cuauht’emoc, G.-C., Monreal-Flores, J. and Martinez, F. (2008) Steroidogenesis in BeWo cells: Role of protein kinase A and benzodiazepines. International Journal of Biochemistry and Cell Biology, 40, 901-908.

[31]   Ridano, M.E., Racca, A.C., Flores-Martín, J., Camolotto, S.A., Magnarelli de Potas, G.M., Genti-Raimondi, S. and Panzetta-Dutari, G.M. (2012) Chlorpyrifos modifies the expression of genes involved in human placental function. Reproductive Toxicology, 33, 331-338.

[32]   Dimon-Gadal, S., Gerbaud, P., Keryer, G., Anderson, W., Evain-Brion, D. and Raynaud, F. (1998) In vitro effects of oxygen derived free radicals on type I and type II cAMPdependent protein kinases. Journal of Biological Chemistry, 273, 22833-22840.

[33]   Grünfeld, H.T. and Bonefeld-Jorgensen, E.C. (2004). Effect of in vitro estrogenic pesticides on human oestrogen receptor alpha and beta mRNA levels. Toxicology Letters, 151, 467-480.

[34]   Ventura, C., Núnez, M.,, Miretb, N., Martinel Lamasa, D., Randib, A., Venturino, A., Rivera, E. and Cocca, C. (2012) Differential mechanisms of action are involved in chlorpyrifos effects in estrogen-dependent or -independent breast cancer cells exposed to low or high concentrations of the pesticide. Toxicology Letters, 213, 184-193.

[35]   Tamura, H., Maness, S.C., Reischmann, K., Dorman, D.C., Gray, L.E. and Gaido, K.W. (2001) Androgen receptor antagonism by the organophosphate insecticide fenitrothion. Toxicological Sciences, 60, 56-62.

[36]   Kojima, H., Katsura, E., Takeuchi, S., Niiyama, K. and Kobayashi, K. (2004) Screening for estrogen and androgen receptor activities in 200 pesticides by in vitro reporter gene assays using Chinese hamster ovary cells. Environmental Health Perspectives, 112, 524-531.

[37]   Sánchez, J.C., López-Zapata, D.F., Francis, L. and de los Reyes, L. (2011) Effects of estradiol and IGF-1 on the sodium calcium exchanger in rat cultured cortical neurons. Cellular and Molecular Neurobiology, 31, 619-627.

[38]   Fiocchetti, M., Ascenzi, P. and Marino, M. (2012) Neuroprotective effects of 17β-estradiol rely on estrogen receptor membrane initiated signals. Frontiers in Physiology, 3, 73.

[39]   Hedges, V.L., Ebner, T.J., Meisel, R.L. and Mermelstein, P.G. (2012) The cerebellum as a target for estrogen action. Frontiers in Neuroendocrinology, 33, 403-411.

[40]   Yamagata, Y., Kanekoc, K., Kasea, D., Ishihara, H., Nairne, A.C., Obatac, K. and Yakamata, I. (2013) Regulation of ERK1/2 mitogen-activated protein kinase by NMDA-receptor-induced seizure activity in cortical slices. Brain Research, 1507, 1-10.

[41]   Kapfhammer, J. P. (2004) Cellular and molecular control of dendritic growth and development of cerebellar purkinje cells. Progress in Histochemistry and Cytochemistry, 39, 131-182.

[42]   Lonze, E. and Ginty, D.D. (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron, 3, 605-623.

[43]   Briz, V., Molina-Molina, J.M., Sánchez-Redondo, S., Fernández, M.F., Grimalt, J.O., Olea, N. and Sunol, C. (2011) Differential estrogenic effects of the persistent organochlorine pesticides dieldrin, endosulfan, and lindane in primary neuronal cultures. Toxicological Sciences, 120, 413-427.

[44]   Fleming, L., Mann, J.B., Bean, J., Briggle, T. and Sanchez-Ramos, J.R. (1994) Parkinson’s disease and brain levels of organochlorine pesticides. Annals of Neurology, 36, 100-103.

[45]   Corrigan, F.M., Wienburg, C.L., Shore, R.F., Daniel, S.E. and Mann, D. (2000) Organochlorine insecticides in substantia nigra in Parkinson’s disease. Journal of Toxicology and Environmental Health A, 59, 229-234.

[46]   Wang, G., Pan, J. and Chen, S.D. (2012) Kinases and kinase signaling pathways: Potential therapeutic targets in Parkinson’s disease. Progress in Neurobiology, 98, 207-221.

[47]   Niijima, H., Nagao, M., Nakajima, M., Takatori, T., Matsuda, Y., Iwase, H. and Kobayashi, M. (1999) Sarin-like and soman-like organophosphorous agents activate PLC gamma in rat brains. Toxicology and Applied Pharmacology, 156, 64-69.

[48]   Schuh, R.A., Lein, P.J., Beckles, R.A. and Jet, D.A. (2002) Noncholinesterase mechanisms of chlorpyrifos neurotoxicity: Altered phosphorylation of Ca2+/cAMP response element binding protein in cultured neurons. Toxicology and Applied Pharmacology, 182, 176-185.

[49]   Slotkin, T.A. and Seidler, F.J. (2009) Protein kinase C is a target for diverse developmental neurotoxicants: Transcriptional responses to chlorpyrifos, diazinon, dieldrin and divalent nickel in PC12 cells. Brain Research, 263, 23-32.

[50]   Moreira, E.G., Xiaozhong, Y., Robinson, J.F., Griffith, W., Woo Hong, S., Beyer, R.P., Bammler, T.K. and Faustman, E.M. (2010) Toxicogenomic profiling in maternal and fetal rodent brains following gestational exposure to chlorpyrifos. Toxicology and Applied Pharmacology, 245, 310-325.

[51]   Jett, D.A., Navoa, R.V., Beckles, R.A. and McLemore, G.L. (2001) Cognitive function and cholinergic neurochemistry in weanling rats exposed to chlorpyrifos. Toxicology and Applied Pharmacology, 174, 89-98.

[52]   Rohlman, D.S., Lasarev, M., Anger, W.K., Scherer, J., Stupfel, J. and McCauley, L. (2007) Neurobehavioral performance of adult and adolescent agricultural workers. Neurotoxicology, 28, 374-380.

[53]   Canadas, F., Cardona, D., Davila, E. and Sanchez-Santed, F. (2005) Long-term neurotoxicity of chlorpyrifos: Spatial learning impairment on repeated acquisition in a water maze. Toxicologycal Sciences, 85, 944-951.

[54]   Verma, S.K., Geetu, R. and Gil, K.D. (2009) Role of muscarinic signal transduction and CREB phosphorylation in dichlorvos-induced memory deficits in rats: An acetylcholine independent mechanism. Toxicology, 256, 175-182.

[55]   RamaRao, G., Acharya, N.J. and Bhattacharya, B.K. (2011) Changes of protein oxidation, calpain and cytoskeletal proteins (alpha tubulin and pNF-H) levels in rat brain after nerve agent poisoning .Toxicology Letters, 203, 227-236.

[56]   Rundhaug, J.E. and Fischer, S.M. (2010) Molecular mechanisms of mouse skin tumor promotion. Cancers, 2, 436-482.

[57]   Terman, B. and Stoletov, K.V. (2001) VEGF and tumor angiogenesis. The Einstein Quarterly Journal of Biology and Medicine, 18, 59-66.

[58]   Bharathi, S.P., Raj, H.M., Jain, S., Banerjee, B.D., Ahmed, T. and Arora, V.K. (2013) Role of pesticides in the induction of tumor angiogenesis. Anticancer Research, 33, 231-240.

[59]   Hreljac, I., Zajc, I., Lah, T. and Filipic, M. (2008) Effects of model organophosphorous pesticides on DNA damage and proliferation of HepG2 cells. Environmental and Molecular Mutagenesis, 49, 360-367.

[60]   Vakonaki, E., Androutsopoulos, V.P., Liesivuori, J., Tsatsakis, A.M. and Spandidos, D.A. (2013) Pesticides and oncogenic modulation. Toxicology, 307, 42-45.

[61]   Griner, E.M. and Kazanietz, M.G. (2007) Protein kinase C and other diacylglycerol effectors in cancer. Nature Reviews Cancer, 7, 281-294.

[62]   Mrema, E.J., Rubino, F.M., Brambilla, G., Moretto, A., Tsatsakis, A.M. and Colosio, C. (2013) Persistent organochlorinated pesticides and mechanisms of their toxicity. Toxicology, 307, 74-88.

[63]   Koutros, S., Freeman, L.E.B., Lubin, J.H., Heltshe, S.L., Andreotti, G., Barry, K.H. and Alavanja, M.C. (2013) Risk of total and aggressive prostate cancer and pesticide use in the agricultural health study. American Journal of Epidemiology, 177, 59-74.

[64]   Cockburn, M., Mills, P., Zhang, X., Zadnick, J., Goldberg, D. and Ritz, B. (2011) Prostate cancer and ambient pesticide exposure in agriculturally intensive areas in California. American Journal of Epidemiology, 173, 1280-1288.

[65]   Tessier, D.M. and Matsumura, F. (2001) Increased ErbB2 tyrosine kinase activity, MAPK phosphorylation, and cell proliferation in the prostate cancer cell line LNCaP following Treatment by Select Pesticides. Toxicological Science, 60, 38-43.

[66]   Han, E.-H., Kim J.Y., Kim, H.-K., Hwang Y.P. and Jeong, H.G. (2008) O,p’-DDT induces cyclooxygenase-2 gene expression in murine macrophages: Role of AP-1 and CRE promoter elements and PI3-kinase/Akt /MAPK signaling pathways. Toxicology and Applied Pharmacology, 233, 333-342.

[67]   Iliopoulos, D., Hirsch, H.A., Wang, G. and Struhl, K. (2011) Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proceedings of the National Academy of Sciences of the United States of America, 108, 13971402.

[68]   Kuraishy, A., Karin, M. and Grivennikov, S. (2011) Tumor promotion via injury and death-induced inflammation. Immunity, 35, 467-477.

[69]   Gosh, N., Chaki, R., Mandal, V. and Mandal, S. (2010) COX-2 as a target for cancer chemotherapy. Pharmacologycal Reports, 62, 233-244.

[70]   Okoumassoun, L.E, Averill-Bates, D., Marion, M. and Denizeau. F. (2003) Possible mechanisms underlying the mitogenic action of heptachlor in rat hepatocytes. Toxicology and Applied Pharmacology, 193, 356-369.

[71]   Bagchi, D., Bagchi, M., Tang, L. and Stohs, S.J. (1997) Comparative in vitro and in vivo protein kinase C activation by selected pesticides and transition metal salts. Toxicology Letters, 91, 31-37.

[72]   Boada, L.D, Zumbado, M., Henríquez-Hernández, L.A, Almeida-González, M., álvarez-León, E.E., Serra-Majem, L. and Luzardo, O.P (2012) Complex organochlorine pesticide mixtures as determinant factor for breast cancer risk: A population-based case-control study in the Canary Islands (Spain). Environmental Health, 11, 1-9.

[73]   Cohn, B.A., Wolff, M.S., Cirillo, P.M. and Sholtz, R.I. (2007) DDT and breast cancer in young women: New data on the significance of age at exposure. Environmental Health Perspectives, 115, 1406-1414.

[74]   Bratton, M.R., Frigo, D.E., Segar, C., Nephew, K.P., McLachlan, J.A., Wiese, T.E. and Burow, M.E. (2012) The organochlorine o,p′-DDT plays a role in coactivator-mediated MAPK crosstalk in MCF-7 breast cancer cells. Environmental Health Perspectives, 120, 1291-1296.

[75]   Longnecker, M.P., Klebanoff, M.A., Brock, J.W., Zhou, H., Gray, K.A., Needham, L.L., et al. (2002) Maternal serum level of 1,1-dichloro-2,2-bis (p-chlorophenyl) ethylene and risk of cryptorchidism hypospadias, and polythelia among male offspring. American Journal of Epidemiology, 155, 313-322.

[76]   López-Carrillo, L., Torres-Sánchez, L., Moline, J., Ireland, K. and Wolff, M.S. (2001) Breast-feeding and serum p, p′DDT levels among Mexican women of childbearing age: A pilot study. Environmental Research, 87, 131-135.

[77]   Valerón, P.F., Pestano, J.J., Luzardo, O.P., Zumbado, M.L., Almeida, M. and Boada, L.D. (2009) Differential effects exerted on human mammary epithelial cells by environmentally relevant organochlorine pesticides either individually or in combination. Chemico-Biological Interactions, 180, 485-491.

[78]   Silva, E., Kabil, A. and Kortenkamp, A. (2010) Crosstalk between non-genomic and genomic signalling pathways—distinct effect profiles of environmental estrogens. Toxicology and Applied Pharmacology, 245, 160-170.

[79]   Cocco, P., Satta, G., Dubois, S., Pili, C., Pilleri, M., Zucca, M. and Boffetta, P. (2013) Lymphoma risk and occupational exposure to pesticides: Results of the epilymph study. Occupational and Environmental Medicine, 70, 91-98.

[80]   Bonner, M.R., Williams, B.A., Rusiecki, J.A., Blair, A., Freeman, L.E.B., Hoppin, J.A. and Alavanja, M.C. (2010) Occupational exposure to terbufos and the incidence of cancer in the agricultural health study. Cancer Causes & Control, 21, 871-877.

[81]   Bomser, J.A., Quistad, G.B. and Casida, J.E. (2002). Chlorpyrifos oxon potentiates diacylglycerol-induced extracellular signal-regulated kinase (ERK 44/42) activation, possibly by diacylglycerol lipase inhibition. Toxicology and Applied pharmacology, 178, 29-36.

[82]   Gwinn, M.R., Whipkey, D.L., Tennant, L.B. and Weston, A. (2005) Differential gene expression in normal human mammary epithelial cells treated with malathion monitored by DNA microarrays. Environmental Health Perspectives, 113, 1046-1051.

[83]   Smeds, J., Berggren, P., Ma, X., Xu, Z., Hemminki, K., and Kumar, R. (2002) Genetic status of cell cycle regulators in squamous cell carcinoma of the oesophagus: The CDKN2A (p16(INK4a) and p14(ARF)) and p53 genes are major targets for inactivation. Carcinogenesis, 23, 645-655.

[84]   Suijkerbuijk, S.J., Vleugel, M., Teixeira, A. and Kops, G.J. (2012) Integration of kinase and phosphatase activeties by BUBR1 ensures formation of stable kinetochoremicrotubule attachments. Developmental Cell, 23, 745-755.

[85]   Ricke, R.M. and van Deursen, J.M. (2011) Correction of microtubule-kinetochore attachment errors: Mechanisms and role in tumor suppression. Seminars in Cell & Developmental Biology, 22, 559-565.

[86]   Ruzzin, J., Petersen, R., Meugnier, E., Madsen, L., Lock, E.J., Lillefosse, H. and Froyland, L. (2010) Persistent organic pollutant exposure leads to insulin resistance syndrome. Environmental Health Perspectives, 118, 465-471.

[87]   Wu, H., Bertrand, K.A., Choi, A.L., Hu, F.B., Laden, F., Grandjean, P. and Sun, Q. (2013) Persistent organic pollutants and type 2 diabetes: A prospective analysis in the nurses’ health study and meta-analysis. Environmental Health Perspectives, 121, 153-161.

[88]   Rignell-Hydbom, A., Rylander, L. and Hagmar, L. (2007) Exposure to persistent organochlorine pollutants and type 2 diabetes mellitus. Human and Experimental Toxicology, 26, 447-452.

[89]   Turyk, M., Anderson, H.A., Knobeloch, L., Imm, P. and Persky, V.W. (2009) Prevalence of diabetes and body burdens of polychlorinated biphenyls, polybrominated diphenyl ethers, and p, p′-diphenyldichloroethene in Great Lakes sport fish consumers. Chemosphere, 75, 674-679.

[90]   Montgomery, M.P., Kamel, F., Saldana, T.M., Alavanja, M.C.R. and Sandler, D.P. (2008) Incident diabetes and pesticide exposure among licensed pesticide applicators: Agricultural health study, 1993-2003. American Journal of Epidemiology, 167, 1235-1246.

[91]   Rezg, R., Mornagui, B., El-Fazaa, S. and Gharbi, N. (2010) Organophosphorus pesticides as food chain contaminants and type 2 diabetes: A review. Trends in Food Science & Technology, 2, 345-357.

[92]   Romero-Navarro, G., Lopez-Aceves, T., Rojas-Ochoa, A., and Fernandez Mejia, C. (2006) Effect of dichlorvos on hepatic and pancreatic glucokinase activity and gene expression, and on insulin mRNA levels. Life Sciences, 78, 1015-1020.

[93]   Rahimi, R. and Abdollahi, M. (2007) A review on the mechanisms involved in hyperglycemia induced by organophosphorus pesticides. Pesticide Biochemistry and Physiology, 88, 115-121.

[94]   Karami-Mohajeri, S. and Abdollahi, M. (2011) Toxic influence of organophosphate, carbamate, and organochlorine pesticides on cellular metabolism of lipids, proteins, and carbohydrates: A systematic review. Human & Experimental Toxicology, 30, 1119-1140.

[95]   Panahi, P., Vosough-Ghanbari, S., Pournourmohammadi, S., Ostad, S.N., Nikfar, S., Minaie, B. and Abdollahi, M. (2006) Stimulatory effects of malathion on the key enzymes activities of insulin secretion in langerhans islets, glutamate dehydrogenase and glucokinase. Toxicology Mechanisms and Methods, 16, 161-167.

[96]   Hectors, T.L.M., Vanparys, C., van der Ven, K., Martens, G.A., Jorens, P.G., Van Gaal, L.F. and Blust, R. (2011) Environmental pollutants and type 2 diabetes: A review of mechanisms that can disrupt beta cell function. Diabetologia, 54, 1273-1290.

[97]   Jatiani, S.S., Baker, S.J., Silverman, L.R. and Reddy, E.P. (2010) JAK/STAT pathways in cytokine signaling and myeloproliferative disorders approaches for targeted therapies. Genes & Cancer, 1, 979-993.

[98]   Esquivel-Sentíes, M.S., Barrera, I., Ortega, A. and Vega, L. (2010) Organophosphorous pesticide metabolite (DEDTP) induces changes in the activation status of human lymphocytes by modulating the interleukin 2 receptor signal transduction pathway. Toxicology and Applied Pharmacology, 248, 122-133.

[99]   Dar, S.A., Das, S., Ramachandran, V.G., Bhattacharya, S.N., Mustafa, M.D., Banerjee, B.D. and Verma, P. (2012) Alterations in T-lymphocyte sub-set profiles and cytokine secretion by PBMC of systemic lupus erythematosus patients upon in vitro exposure to organochlorine pesticides. Journal of Immunotoxicology, 9, 85-95.

[100]   Duramad, P., Tager, I.B., Leikauf, J., Eskenazi, B. and Holland, N.T. (2006) Expression of Th1/Th2 cytokines in human blood after in vitro treatment with chlorpyrifos, and its metabolites, in combination with endotoxin LPS and allergen Der p1. Journal of Applied Toxicology, 26, 458-465.

[101]   Li, Q. (2007) New mechanism of organophosphorus pesticide-induced immunotoxicity. Journal of Nippon Medical School, 74, 92-105.

[102]   Esquivel-Sentíes, M.S. and Vega, L. (2012) Organophosphorous pesticides metabolite reduces human T CD8 homeostasis and proliferation by inducing cellular death. Journal of Environmental & Analytical Toxicology.

[103]   Elsharkawy, E.E., Yahia, D. and El-Nisr, N.A. (2013) Sub-chronic exposure to chlorpyrifos induces hematological, metabolic disorders and oxidative stress in rat: Attenuation by glutathione. Environmental Toxicology and Pharmacology, 35, 218-227.

[104]   Franco, R., Sánchez-Olea, R., Reyes-Reyes, E.M. and Panayiotidis, M.I. (2009) Environmental toxicity, oxidative stress and apoptosis: Menage a trois. Mutation Research/ Genetic Toxicology and Environmental Mutagenesis, 674, 3-22.

[105]   Limón-Pacheco, J. and Gonsebatt, M.E. (2009) The role of antioxidants and antioxidant-related enzymes in protective responses to environmentally induced oxidative stress. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 674, 137-147.

[106]   Song, M.O., Lee, C.H., Yang, H.O. and Freedman, J.H. (2012). Endosulfan upregulates AP-1 binding and AREmediated transcription via ERK1/2 and p38 activation in HepG2 cells. Toxicology, 292, 23-32.

[107]   Lushchak, V.I. (2011) Adaptive response to oxidative stress: Bacteria, fungi, plants and animals. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 153, 175-190.

[108]   Mrema, E.J., Rubino, F.M., Brambilla, G., Moretto, A., Tsatsakis, A.M. and Colosio, C. (2013) Persistent organochlorinated pesticides and mechanisms of their toxicity. Toxicology, 307, 74-88.

[109]   Zucchini-Pascal, N., de Sousa, G., Pizzol, J. and Rahmani, R. (2011) Molecular investigation of the effects of lindane in rat hepatocytes: Microarray and mechanistic studies. Food and Chemical Toxicology, 49, 3128-3135.

[110]   Ojha, A., Yaduvanshi, S.K. and Srivastava, N. (2011) Effect of combined exposure of commonly used organophosphate pesticides on lipid peroxidation and antioxidant enzymes in rat tissues. Pesticide Biochemistry and Physiology, 99, 148-156.

[111]   Uchendu, C.H., Ambali, S.F. and Ayo, J.O. (2012) The organophpsphate, chlorpyrifos, oxidative stress and the role of some antioxidants: A review. African Journal of Agricultural Research, 7, 2720-2728.

[112]   Lee, J.E., Park, J.H., Shin, I.C. and Koh, H.C. (2012) Reactive oxygen species regulated mitochondria-mediated apoptosis in PC12 cells exposed to chlorpyrifos. Toxicology and Applied Pharmacology, 63, 148-162.

[113]   Ki, Y.W., Park, J.H., Lee, J.E., Shin, I.C. and Koh, H.C. (2013) JNK and p38 MAPK regulate oxidative stress and the inflammatory response in chlorpyrifos-induced apoptosis. Toxicology Letters, 218, 235-245.

[114]   Liu, H., Liu, J., Xu, L., Zhou, S., Li, L. and Liu, W. (2010) Enantioselective cytotoxicity of isocarbophos is mediated by oxidative stress-induced JNK activation in human hepatocytes. Toxicology, 276, 115-121.

[115]   Vaissière, T., Sawan, C. and Herceg, Z. (2008) Epigenetic interplay between histone modifications and DNA methylation in gene silencing. Mutation Research/Reviews in Mutation Research, 659, 40-48.

[116]   Bannister, A.J. and Kouzarides, T. (2011) Regulation of chromatin by histone modifications. Cell Research, 21, 381-395.

[117]   Zhang, X., Wallace, A.D., Du, P., Lin, S., Baccarelli, A.A., Jiang, H. and Hou, L. (2012) Genome-wide study of DNA methylation alterations in response to Diazinon exposure in vitro. Environmental Toxicology and Pharmacology, 343, 959-968.

[118]   Kota, S.K. and Feil, R. (2010) Epigenetic transitions in germ cell development and meiosis. Developmental Cell, 19, 675-686.

[119]   Oliva, R. and Dixon, G.H. (1991) Vertebrate protamine genes and the histone to protamine replacement reaction. Progress in Nucleic Acid Research and Molecular Biology, 40, 25-94.

[120]   Sánchez-Pena, L.C., Reyes, B.E., López-Carrillo, L., Recio, R., Morán-Martínez, J., Cebrián, M.E. and QuintanillaVega, B. (2004) Changes on sperm chromatin structure in organophosphorus agricultural workers. Toxicology and Applied Pharmacology, 196, 108-113.

[121]   Pina-Guzmán, B., Solis-Heredia, M.J. and QuintanillaVega, B. (2005) Diazinon alters sperm chromatin structure in mice by phosphorylating nuclear protamines. Toxicology and Applied Pharmacology, 202, 189-198.