PESTICIDE INDUCED DIFFERENTIATION OF BREAST CANCER CELLS

Summary

Principal 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

  1. ncbi Immunotoxic effects of short-term atrazine exposure in young male C57BL/6 mice
    Nikolay 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
  2. ncbi Alteration of neurotrophins in the hippocampus and cerebral cortex of young rats exposed to chlorpyrifos and methyl parathion
    Angela 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
  3. ncbi Human carboxylesterases and their role in xenobiotic and endobiotic metabolism
    Matthew 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
  4. ncbi Evaluation of the 'side door' in carboxylesterase-mediated catalysis and inhibition
    Timothy 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
  5. ncbi Alteration of dopamine uptake into rat striatal vesicles and synaptosomes caused by an in vitro exposure to atrazine and some of its metabolites
    Muhammad 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
  6. ncbi Direct effects of manganese compounds on dopamine and its metabolite Dopac: an in vitro study
    Shannon 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
  7. ncbi Alterations in amphetamine-stimulated dopamine overflow due to the Nurr1-null heterozygous genotype and postweaning isolation
    Talisha M Moore
    Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi 39762, USA
    Synapse 62:764-74. 2008
  8. ncbi Effect of different administration paradigms on cholinesterase inhibition following repeated chlorpyrifos exposure in late preweanling rats
    Russell 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
  9. ncbi Inhibition of carboxylesterase 1 is associated with cholesteryl ester retention in human THP-1 monocyte/macrophages
    J Allen Crow
    Department of Basic Sciences, Mississippi State University, Mississippi State, MS 39762 6100, USA
    Biochim Biophys Acta 1781:643-54. 2008
  10. ncbi Global liver proteomics of rats exposed for 5 days to phenobarbital identifies changes associated with cancer and with CYP metabolism
    Mary 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

Scientific Experts

  • Nikolay M Filipov
  • Russell Carr
  • Peter L Ryan
  • Jeffrey B Eells
  • Matthew K Ross
  • J Allen Crow
  • Mary B Dail
  • Philip M Potter
  • Angela M Betancourt
  • Stephen J Godin
  • Janice E Chambers
  • Abdolsamad Borazjani
  • Shane C Burgess
  • Frank O Johnson
  • Talisha M Moore
  • Timothy M Streit
  • Muhammad M Hossain
  • Shannon C Sistrunk
  • Lesya M Pinchuk
  • A Coban
  • Steven R Gwaltney
  • Edward J Scollon
  • Michael J DeVito
  • Michael F Hughes
  • Kanchana S Thanthiriwatte
  • Sumalee Givaruangsawat
  • Carole A Nail
  • Shellaine E Lentz
  • Brandy L Middleton
  • Monika Wierdl
  • M Jason Hatfield
  • L Allen Shack
  • Mirae Cade
  • Timothy Brown
  • Edward C Meek
  • Sang Ryul Lee
  • Jennifer Wagner
  • Sang-Ryul Lee
  • Jeffrey Baravik

Detail Information

Publications24

  1. ncbi Immunotoxic effects of short-term atrazine exposure in young male C57BL/6 mice
    Nikolay 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...
  2. ncbi Alteration of neurotrophins in the hippocampus and cerebral cortex of young rats exposed to chlorpyrifos and methyl parathion
    Angela 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...
  3. ncbi Human carboxylesterases and their role in xenobiotic and endobiotic metabolism
    Matthew 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...
  4. ncbi Evaluation of the 'side door' in carboxylesterase-mediated catalysis and inhibition
    Timothy 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...
  5. ncbi Alteration of dopamine uptake into rat striatal vesicles and synaptosomes caused by an in vitro exposure to atrazine and some of its metabolites
    Muhammad 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
    ....
  6. ncbi Direct effects of manganese compounds on dopamine and its metabolite Dopac: an in vitro study
    Shannon 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...
  7. ncbi Alterations in amphetamine-stimulated dopamine overflow due to the Nurr1-null heterozygous genotype and postweaning isolation
    Talisha M Moore
    Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi 39762, USA
    Synapse 62:764-74. 2008
    ....
  8. ncbi Effect of different administration paradigms on cholinesterase inhibition following repeated chlorpyrifos exposure in late preweanling rats
    Russell 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...
  9. ncbi Inhibition of carboxylesterase 1 is associated with cholesteryl ester retention in human THP-1 monocyte/macrophages
    J 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...
  10. ncbi Global liver proteomics of rats exposed for 5 days to phenobarbital identifies changes associated with cancer and with CYP metabolism
    Mary 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
    ....
  11. ncbi Repeated developmental exposure to chlorpyrifos and methyl parathion causes persistent alterations in nicotinic acetylcholine subunit mRNA expression with chlorpyrifos altering dopamine metabolite levels
    Jeffrey 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
    ....
  12. ncbi In vitro atrazine exposure affects the phenotypic and functional maturation of dendritic cells
    Lesya 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...
  13. ncbi Identification of rat and human cytochrome p450 isoforms and a rat serum esterase that metabolize the pyrethroid insecticides deltamethrin and esfenvalerate
    Stephen 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...
  14. ncbi Photonic monitoring in real time of vascular endothelial growth factor receptor 2 gene expression under relaxin-induced conditions in a novel murine wound model
    Peter 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...
  15. ncbi Hydrolytic metabolism of pyrethroids by human and other mammalian carboxylesterases
    Matthew 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...
  16. ncbi Excitation spectra of dibenzoborole containing pi-electron systems: controlling the electronic spectra by changing the p(pi)-pi* conjugation
    Kanchana 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...
  17. ncbi Determination of atrazine and its metabolites in mouse urine and plasma by LC-MS analysis
    Matthew 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
    ....
  18. ncbi Effect of developmental exposure to chlorpyrifos on the expression of neurotrophin growth factors and cell-specific markers in neonatal rat brain
    Angela M Betancourt
    Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University, 39762, USA
    Toxicol Sci 92:500-6. 2006
    ....
  19. ncbi Species differences in the in vitro metabolism of deltamethrin and esfenvalerate: differential oxidative and hydrolytic metabolism by humans and rats
    Stephen J Godin
    Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    Drug Metab Dispos 34:1764-71. 2006
    ....
  20. ncbi Dopaminergic toxicity associated with oral exposure to the herbicide atrazine in juvenile male C57BL/6 mice
    A 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
    ....
  21. ncbi Dopaminergic toxicity of the herbicide atrazine in rat striatal slices
    Nikolay 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...
  22. ncbi Hydrolysis of pyrethroids by human and rat tissues: examination of intestinal, liver and serum carboxylesterases
    J 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...
  23. ncbi Spatial distribution of CYP2B1/2 messenger RNA within the rat liver acinus following exposure to the inducers phenobarbital and dieldrin
    Mary 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...
  24. ncbi Developmental chlorpyrifos and methyl parathion exposure alters radial-arm maze performance in juvenile and adult rats
    Frank 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
    ....