Superfund Research Program

Membrane efflux pumps and hormonal activity of organochlorine contaminants in New York Harbor sediments

Project Leader: Avrom Caplan
Grant Number: P42ES007384
Funding Period: 1995 - 2006

Project-Specific Links

Final Progress Reports

Year:   2005  1999 

This project explores the hypothesis that chlorinated hydrocarbons deposited in the environment exhibit hormonal activity including estrogenicity. Harbor sediment samples and pure chemicals are being tested in vitro using assay systems of isolated human cell lines. These assays allow rapid efficient screening of an array of chemicals and of chemical mixtures as they occur in hazardous waste sites. Detection of a range of hormonal and anti-hormonal activities of environmental contaminants will reflect their potential for public health risks, especially for reproductive dysfunction and cancer. Exposure may affect more than one hormone system, an outcome that could be missed by evaluating estrogenic activity alone. Data obtained may support a hypothesis that estrogenic and progestagenic activity of these agents may be a mechanism through which chlorinated hydrocarbons in the environment enhance the risk of breast cancer and possibly other cancers in exposed populations.

In vitro assays for hormonal activities are being used to assess the hormonal activity of organochlorines that contaminate Superfund sites, including the Hudson River. These studies employ human cell lines Ishikawa-Var I (estrogenicity), T47D (progestagenicity), and MCF-7 breast tumor cells to measure hormonal responses. Compounds exhibiting estrogenicity include Kepone (chlordecone), 1-hydroxychlordene, endosulfan, b-BHC and o,p'-DDT, bisphenol-A, technical grade DDT, Aroclor 1221, five hydroxy-PCB congeners, fenvalerate, sumithrin, and the flavonoid compounds apigenin, chrysin, kaempferol, and quercetin. No estrogenicity was seen in our assays for atrazine, p,p'-DDE, g-BHC, a-chlordane, g-chlordane, dieldrin and methoxychlor, butylated hydroxyanisole, lead acetate, phthalic acid diethyl ester (a plasticizer), 1,2-benzanthracene and fluoranthene nor for three PCB congeners and two additional hydroxy-PCBs. Combinations of two hydroxy-PCBs and of four pesticides showed approximately additive estrogenicity (endosulfan, dieldrin, Kepone, o,p'-DDT). Certain mixtures of chlordane components and of PAH compounds were estrogenic. In tests of antiestrogenic activity, 1,2-benzanthracene was an antagonist but other compounds were not, including PCBs.

Results on progestagenic response have been obtained for 39 compounds, using the T47D cell line. Dieldrin and three phytoestrogens were progestagenic. Other organochlorines, PAH and related compunds were not progestagenic. In assays for anti-progestagenic effects, activities were found for endosulfan, methoxychlor, dieldrin, two pyrethroids, and five PAH which were strongly anti-progestagenic (anthracene, phenanthrene, benzo[a]pyrene, fluoranthene, benzanthracene).

In addition, Saccharomyces cerevisiae with a b-gal reporter has been used to assess estrogenicity as well as mechanism of action of these compounds. Researchers are currently analyzing the role of multidrug resistance pumps as effectors of intracellular estrogen concentration. Results suggest multidrug resistance pumps affect the estrogenicity of PCBs by affecting their efflux or the efflux of estradiol from the cell.