A primary goal of our research is the identification of alterations in gene expression in human reproductive cell lines which are mediated by prototype Superfund chemicals. Our focus is to develop in vitro models to reproduce some of the in vivo events involved in the development and function of human placenta, uterus and prostate. In the present funding period, studies have focused on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), benzo(a)pyrene (BaP), and the polychlorinated biphenyl (PCB) congeners 3,3',4,4'-tetrachlorobiphenyl (TCB) and 2,2'4,4'5,5'- hexachlorobiphenyl (HCB) as prototypes for defining Ah receptor (AhR)- dependent effects. Our hypothesis is that TCDD, PCBs and BaP alter paracrine and autocrine growth regulatory networks which are recognized to be important for proliferation, migration/invasiveness and hormone responsiveness. Dose-response relationships have been established for each gene product to identify which endpoints are the most sensitive biomarkers in relationship to the induction of cytochrome P450 CYPIA1. The next funding period will focus on evaluation of the effects of PCB congeners which are relevant to human exposure and which may have both AhR-dependent and -independent mechanisms of action. The first Specific Aim is to identify mechanisms by which TCDD, PCBs and BaP induce the expression of the pro-inflammatory cytokines in human uterine and placental cell lines which may underlie the promotion of uterine disease and impaired placental development. The second Specific Aim is to characterize the effects of TCDD, PCBs and BaP on the migration/invasive activity of placental and uterine cells relative to changes in cell adhesion molecule interactions with extracellular matrix and cytoskeletal microfilaments.
The Third Aim i s to investigate the potential role of the enzymes prostaglandin H synthase (PGHS)-1 and -2 in the metabolic activation and toxic effects of BaP and PCB compounds. PGHS enzymes, constitutively expressed and induced, may provide an alternative pathway to CYPIAI for peroxidative metabolism and oxidative stress-induced alterations in gene expression.
The final Aim will investigate whether human prostate cell lines are targets for changes in proliferation, migration and growth factor gene expression, which can be mechanisms for the promotion of prostate disease. In summary, this research will identify and validate sensitive biomarkers for exposure, as well as establish molecular and cellular mechanisms for altered uterine, placental and prostate function.

Project Start
2001-04-01
Project End
2002-03-31
Budget Start
Budget End
Support Year
7
Fiscal Year
2001
Total Cost
$131,644
Indirect Cost
Name
University of Florida
Department
Type
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Mangal, Naveen; James, Margaret O; Stacpoole, Peter W et al. (2018) Model Informed Dose Optimization of Dichloroacetate for the Treatment of Congenital Lactic Acidosis in Children. J Clin Pharmacol 58:212-220
Jiang, Yu; Milavetz, Gary; James, Margaret O et al. (2017) A Mechanism-Based Pharmacokinetic Enzyme Turnover Model for Dichloroacetic Acid Autoinhibition in Rats. J Pharm Sci 106:1396-1404
Shroads, Albert L; Coats, Bonnie S; Langaee, Taimour et al. (2015) Chloral hydrate, through biotransformation to dichloroacetate, inhibits maleylacetoacetate isomerase and tyrosine catabolism in humans. Drug Metab Pers Ther 30:49-55
Shroads, A L; Coats, B S; McDonough, C W et al. (2015) Haplotype variations in glutathione transferase zeta 1 influence the kinetics and dynamics of chronic dichloroacetate in children. J Clin Pharmacol 55:50-5
James, Margaret O; Kleinow, Kevin M (2014) Seasonal influences on PCB retention and biotransformation in fish. Environ Sci Pollut Res Int 21:6324-33
Garcia-Reyero, Natàlia; Martyniuk, Christopher J; Kroll, Kevin J et al. (2013) Transcriptional signature of progesterone in the fathead minnow ovary (Pimephales promelas). Gen Comp Endocrinol 192:159-69
Kocerha, Jannet; Prucha, Melinda S; Kroll, Kevin J et al. (2010) Regulation of steroidogenic acute regulatory protein transcription in largemouth bass by orphan nuclear receptor signaling pathways. Endocrinology 151:341-9
Tan, Xiaobing; Yim, Sun-Young; Uppu, Prasanna et al. (2010) Enhanced bioaccumulation of dietary contaminants in catfish with exposure to the waterborne surfactant linear alkylbenzene sulfonate. Aquat Toxicol 99:300-8
Nyagode, Beatrice A; James, Margaret O; Kleinow, Kevin M (2009) Influence of dietary Coexposure to benzo(a)pyrene on the biotransformation and distribution of 14C-methoxychlor in the channel catfish (Ictalurus punctatus). Toxicol Sci 108:320-9
Rauschenberger, R Heath; Sepulveda, Maria S; Wiebe, Jon J et al. (2009) Nutrient and organochlorine pesticide concentrations in American alligator eggs and their associations with clutch viability. J Aquat Anim Health 21:249-61

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