Research Topics
| PESTICIDE INDUCED DIFFERENTIATION OF BREAST CANCER CELLSSummaryPrincipal Investigator: S Willard Affiliation: Mississippi State University Country: USA Abstract: Many pesticides, synthetic chemicals used in production agriculture to control insects (insecticides), fungi (fungicides) and weeds (herbicides), have been shown to have estrogenic activity in mammalian systems, including neoplasias of the breast. Epidemiological evidence from studies of rural communities have suggested that direct human expc, sure to these agents may account, at least in part, for the increased incidences for breast, endometrial and ovarian cancers in these sub-populations. With the pervasive use of these chemicals in production agriculture, exposure is not isolated to rural communities but may also manifest in urban societies via run-off in drinking water or chemical residues, remaining on vegetables and fruits. While pesticide-induced carcinogenesis has been suggested based on both in vivo and in vitro evidence, a consensus on whether exposure to relatively weak estrogenic pesticides is in fact physiologically relevant or even ultimately harmful has yet to be reached. Moreover, the dual actions of some endocrine-active pesticides as potential agonists and antagonists have resulted in a general confusion in the literature regarding the role that these compounds may play in cancer progression. While evidence mounts on both sides of the debate concerning the relevance of endocrine-active pesticides on cancer progression, it is becoming increasingly clear that endogenous cellular mechanisms exist which may augment the actions of pesticides, in addition to the fact that pesticides are more often found in mixtures not singularly, suggesting that low potency of one chemical by itself may be a poor measure of what can occur in vivo following pesticide exposure. An alternate explanation for the reported varied effects of endocrine-active pesticides on the mechanisms regulating cancer progression, particularly those influencing estrogen-sensitive pathways, is the fact that most cancer cell populations are heterogeneous and not homogeneous. Even in presumably homogeneous cancer cell lines, differential responses among individual cells have been observed and can mirror the heterogeneous nature of primary tumors. These differentially responsive subpopulations within a population of cancer ceils have been implicated as being responsible for the development of tumoral chemotherapeutic "resistance," and the subsequent recurrence of primary tumors post-treatment. However, the role of endocrine-active pesticides as potential effectors and/or differential regulators of individual cancer cells within a population have yet to be examined. The case for endocrine-active pesticides as variable modulators of cancer development may be greatly impacted by findings that might demonstrate differential responsiveness among individual cells within a population exposed to such agents alone or in relevant mixtures. The goal of this study is to examine how estrogenic and non-estrogenic endocrine-active pesticides alone or in combination (i.e., mixtures) may augment or inhibit endocrine responses in breast cancer cells, and whether these interactions might result in a differential selection (directly or indirectly) for an invasive phenotype. The rationale for this is that by understanding how pesticide mixtures may alter the endocrine behavior of cancerous cells, we may better understand the implications of pesticide exposure in relation to cancer risk. Moreover, by clarifying the responses of cells to pesticides within heterogeneous cancer cell societies, we may better appreciate how/why tumors become resistant or highly sensitive to chemotherapeutic or other targeted endocrine agents. The specific hypothesis to be tested is that pesticides alone and in combination can re-model breast cancer cell populations. To pursue the research objectives of this application, the following four Specific Aims have been formulated: 1. To examine the estrogen receptor- and non-estrogen receptor-mediated effects of pesticides (alone and in combination) on estrogen receptor expression and estrogen-sensitive gene transcription in breast cancer cells. 2. To elucidate whether endogenous cellular pathways may influence the actions of pesticides (alone or in mixtures) on estrogen-regulated gene transcription in breast cancer cells. 3. To determine whether endocrine-active pesticides (alone or in mixtures) may differentially regulate the responsiveness of subpopulations of cells within cancer cell societies. 4. To evaluate whether selected subpopulations of cancer cells (e.g., tamoxifen resistant phenotypes) are more or less responsive to endocrine-active pesticides (alone or in mixtures). Funding Period: 2002-09-26 - 2007-08-31 more information: NIH RePORT Top Publications
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Immunotoxic effects of short-term atrazine exposure in young male C57BL/6 miceNikolay M Filipov
Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi 39762 6100, USA
Toxicol Sci 86:324-32. 2005..Thus, ATR exposure appears to be detrimental to the immune system of juvenile mice by decreasing cellularity and affecting lymphocyte distribution, with certain effects persisting long after exposure has been terminated...- Alteration of neurotrophins in the hippocampus and cerebral cortex of young rats exposed to chlorpyrifos and methyl parathionAngela M Betancourt
Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762, USA
Toxicol Sci 100:445-55. 2007..These results indicate that repeated developmental OP exposure during the postnatal period alters NGF and BDNF in the cortex and the hippocampus and the patterns of these alterations differ between regions... - Human carboxylesterases and their role in xenobiotic and endobiotic metabolismMatthew K Ross
Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, MS 39762, USA
J Biochem Mol Toxicol 21:187-96. 2007..Identification of the factors that lead to altered CE activities in HLMs will be important to characterize since several pharmaceutical agents, environmental toxicants, and endobiotics are metabolized by these enzymes... 
Evaluation of the 'side door' in carboxylesterase-mediated catalysis and inhibitionTimothy M Streit
Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762, USA
Biol Chem 389:149-62. 2008..In summary, the L362R mutant CE markedly slowed the rate of ester hydrolysis and was less sensitive to OP inhibition. The apparent causes of the diminished catalysis are discussed...
Alteration of dopamine uptake into rat striatal vesicles and synaptosomes caused by an in vitro exposure to atrazine and some of its metabolitesMuhammad M Hossain
Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, MS 39762 6100, USA
Toxicology 248:52-8. 2008....- Direct effects of manganese compounds on dopamine and its metabolite Dopac: an in vitro studyShannon C Sistrunk
Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USA
Environ Toxicol Pharmacol 23:286-96. 2007..Thus, a potential additional mechanism for the neurotoxic effects of environmentally-relevant forms of Mn, MnPO(4) in particular, is the generation of reactive DA intermediates... - Alterations in amphetamine-stimulated dopamine overflow due to the Nurr1-null heterozygous genotype and postweaning isolationTalisha M Moore
Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi 39762, USA
Synapse 62:764-74. 2008.... - Effect of different administration paradigms on cholinesterase inhibition following repeated chlorpyrifos exposure in late preweanling ratsRussell L Carr
Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi 39762, USA
Toxicol Sci 106:186-92. 2008..Inhibition in the low volume CPS-DMSO group was generally between that in the CPS-oil groups and the high volume CPS-DMSO group. These data suggest that using DMSO as a vehicle for CPS may alter the level of brain ChE inhibition... - Inhibition of carboxylesterase 1 is associated with cholesteryl ester retention in human THP-1 monocyte/macrophagesJ Allen Crow
Department of Basic Sciences, Mississippi State University, Mississippi State, MS 39762 6100, USA
Biochim Biophys Acta 1781:643-54. 2008..Thus, exposure to OP pesticides, which results in the inhibition of CES1, may also inhibit macrophage RCT, an important process in the regression of atherosclerosis... - Global liver proteomics of rats exposed for 5 days to phenobarbital identifies changes associated with cancer and with CYP metabolismMary B Dail
Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi 39762, USA
Toxicol Sci 106:556-69. 2008.... - Repeated developmental exposure to chlorpyrifos and methyl parathion causes persistent alterations in nicotinic acetylcholine subunit mRNA expression with chlorpyrifos altering dopamine metabolite levelsJeffrey B Eells
Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, MS 39762, USA
Neurotoxicol Teratol 31:98-103. 2009.... - In vitro atrazine exposure affects the phenotypic and functional maturation of dendritic cellsLesya M Pinchuk
Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762, USA
Toxicol Appl Pharmacol 223:206-17. 2007..Thus, our data suggest that atrazine directly targets DC maturation and that toxicants such as atrazine that efficiently remove MHC-I molecules from the DC surface are likely to contribute to immune evasion... - Identification of rat and human cytochrome p450 isoforms and a rat serum esterase that metabolize the pyrethroid insecticides deltamethrin and esfenvalerateStephen J Godin
United States Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Resource Laboratory, Experimental Toxicology Division, Pharmacokinetics Branch, Research Triangle Park, NC 27711, USA
Drug Metab Dispos 35:1664-71. 2007..Furthermore, these studies show that the metabolic elimination of deltamethrin and esfenvalerate in blood may be important to their disposition in rats but not in humans... - Photonic monitoring in real time of vascular endothelial growth factor receptor 2 gene expression under relaxin-induced conditions in a novel murine wound modelPeter L Ryan
Department of Animal and Dairy Sciences, College of Agriculture and Life Sciences, Mississippi State University, Mississippi State, Mississippi 39762, USA
Ann N Y Acad Sci 1041:398-414. 2005..e., VEGF-luc mouse) to study relaxin-induced gene expression in normal (i.e., wound healing) or tumorigenic tissues in real time... - Hydrolytic metabolism of pyrethroids by human and other mammalian carboxylesterasesMatthew K Ross
Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, PO Box 6100 Mississippi State, MS 39762-6100, USA
Biochem Pharmacol 71:657-69. 2006..While there are likely other esterases in human liver that hydrolyze pyrethroids, the results of this study clearly demonstrate that hCE-1 and hCE-2 are human pyrethroid-hydrolyzing CEs... - Excitation spectra of dibenzoborole containing pi-electron systems: controlling the electronic spectra by changing the p(pi)-pi* conjugationKanchana S Thanthiriwatte
Department of Chemistry, Center for Environmental Health Sciences, Mississippi State University, Mississippi State, Mississippi 39762, USA
J Phys Chem A 110:2434-9. 2006..In addition, we investigated and analyzed the nature of these electronic excitations using attachment/detachment density plots, with which we characterized the changes in electron density that arose from the excitations... - Determination of atrazine and its metabolites in mouse urine and plasma by LC-MS analysisMatthew K Ross
Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762, USA
Anal Biochem 351:161-73. 2006.... - Effect of developmental exposure to chlorpyrifos on the expression of neurotrophin growth factors and cell-specific markers in neonatal rat brainAngela M Betancourt
Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University, 39762, USA
Toxicol Sci 92:500-6. 2006.... - Species differences in the in vitro metabolism of deltamethrin and esfenvalerate: differential oxidative and hydrolytic metabolism by humans and ratsStephen J Godin
Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Drug Metab Dispos 34:1764-71. 2006.... - Dopaminergic toxicity associated with oral exposure to the herbicide atrazine in juvenile male C57BL/6 miceA Coban
Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi 39762 6100, USA
J Neurochem 100:1177-87. 2007.... - Dopaminergic toxicity of the herbicide atrazine in rat striatal slicesNikolay M Filipov
Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, MS 39762 6100, USA
Toxicology 232:68-78. 2007..Taken together, results from this study suggest that ATR decreases tissue DA levels not by affecting TH activity, but possibly by interfering with the vesicular storage and/or cellular uptake of DA... - Hydrolysis of pyrethroids by human and rat tissues: examination of intestinal, liver and serum carboxylesterasesJ Allen Crow
Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, PO Box 6100 Mississippi State, MS 39762 6100, USA
Toxicol Appl Pharmacol 221:1-12. 2007..Moreover, hepatic cytosolic and microsomal hydrolytic metabolism should each be considered during the development of pharmacokinetic models that predict the disposition of pyrethroids and other esterified compounds... - Spatial distribution of CYP2B1/2 messenger RNA within the rat liver acinus following exposure to the inducers phenobarbital and dieldrinMary B Dail
Center for Environmental Health Sciences and Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762, USA
Toxicol Sci 99:35-42. 2007..It also indicates the importance of examining xenobiotic metabolism in the liver in light of its nonhomogeneous, zoned microenvironment... - Developmental chlorpyrifos and methyl parathion exposure alters radial-arm maze performance in juvenile and adult ratsFrank O Johnson
Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi 39762, USA
Toxicol Sci 109:132-42. 2009....