CORRESPONDENCE

Re: 1,1-Dichloro-2,2-bis- (p-chlorophenyl)ethylene and Polychlorinated Biphenyls and Breast Cancer: Combined Analysis of Five U.S. Studies

Leslie W. Glustrom, Rachel M. Mitton-Fry, Deborah S. Wuttke

Affiliations of authors: L. W. Glustrom, R. M. Mitton-Fry, D. S. Wuttke, Department of Chemistry and Biochemistry, University of Colorado, Boulder.

Correspondence to: Deborah S. Wuttke, Ph.D., Department of Chemistry and Biochemistry, UCB 215, University of Colorado-Boulder, Boulder, CO 80309 (e-mail: deborah.wuttke{at}colorado.edu).

Many studies over the years, including a number that have appeared in the Journal, examined the possible connection between environmental pollutants and the development of breast cancer. Recently, the Journal published the combined analysis of five studies evaluating the association of levels of 2,2-bis (p-chlorophenyl)-1,1-dichloroethylene (DDE) and polychlorinated biphenyls in blood plasma or serum with breast cancer risk (1). In these studies, DDE, a metabolite of 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT), is used as a marker for DDT exposure. The majority of studies published to date using DDE as a marker do not support the hypothesis that elevated exposure to DDT increases the risk of breast cancer. It should be asked, however, whether residual DDE levels are an appropriate marker for determining the estrogenic component of DDT exposures.

A substantial body of research indicates that it is not chemicals such as DDT or DDE (which contain a chlorinated phenyl ring) that are estrogenic compounds and, therefore, potentially carcinogenic. Rather, compounds capable of triggering an estrogenic response typically contain a hydroxylated phenyl ring, a configuration that allows the chemical to bind to and activate the estrogen receptor. It should be considered, therefore, that it is not DDT or DDE, but hydroxylated metabolites of these compounds (Fig. 1Go) that are acting as estrogenic compounds. Then, because of their increased polarity, these metabolites are cleared from the system. [We note that in one study of DDT metabolism, 80% of the DDT metabolites were classified as "polar metabolites" but not further characterized; see Table VI in (2).]



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Fig. 1. Structures of key compounds. The phenolic hydroxyl (OH) in estradiol (*) is key for receptor binding and estrogenic activity. Compounds like 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT) and 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (DDE) have a chlorine in this position, whereas hydroxylated metabolites like 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE) and dihydroxy-DDE have the key phenolic group and display both increased estrogen receptor binding and estrogenic activity.

 
Studies spanning more than six decades [for example, see (3–6)] have established the importance of a hydroxylated phenyl ring for estrogen receptor binding and estrogenic activity. For example, an extensive analysis of structure–activity relationships for estrogen receptor ligands published in 1999 (4) concluded that "A phenolic hydroxy group, which mimics the 3-OH on the A-ring of estradiol (and at the corresponding position of nonsteroidal estrogen ligands), appears repeatedly as the most important factor in receptor–ligand interactions."

The importance of a hydroxylated phenyl ring for estrogenic activity is reinforced by the crystal structures of the ligand-binding domains of both estrogen receptor {alpha} (ER{alpha}) and ER{beta} that have been published in recent years (7). All of the structures indicate that the key phenolic hydroxyl of the bound ligands is hydrogen bonded to a highly conserved arginine residue and a glutamic acid residue in the ligand-binding domain (e.g., arginine-394 and glutamic acid-353 in ER{alpha}). This hydrogen bonding interaction acts as a clamp on the phenolic hydroxyl, and it is unlikely that the chlorinated phenyl ring of DDT or DDE is able to fulfill this interaction.

We also note that, for a given exposure, an individual with a more active hydroxylation response (e.g., through the cytochrome P450 system) would have a greater exposure to hydroxylated (and presumably, therefore, estrogenic) metabolic products but a lower residual level of DDE.

For all of these reasons, we question whether using residual levels of DDE (or other compounds with a chlorinated phenyl ring, like the polychlorinated biphenyls) is an accurate measure of exposure to estrogenic compounds.

REFERENCES

1 Laden F, Collman G, Iwamoto K, Alberg AJ, Berkowitz GS, Freudenheim JL, et al. 1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene and polychlorinated biphenyls and breast cancer: combined analysis of five U.S. studies. J Natl Cancer Inst 2001;93:768–76.[Abstract/Free Full Text]

2 Kapoor IP, Metcalf RL, Nystrom RF, Sangha GK. Comparative metabolism of methoxychlor, methiochlor, and DDT in mouse, insects, and in a model ecosystem. J Agric Food Chem 1970;18:1145–52.[Medline]

3 Dodds EC, Lawson W. Molecular structure in relation to oestrogenic activity. Compounds without a phenanthrene nucleus. Proc R Soc Lond B Biol Sci 1938;125:222–32.

4 Gao H, Katzenellenbogen JA, Garg R, Hansch C. Comparative QSAR analysis of estrogen receptor ligands. Chem Rev 1999;99:723–44.[Medline]

5 Blair RM, Fang H, Branham WS, Hass BS, Dial SL, Moland CL, et al. The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands. Toxicol Sci 2000;54:138–53.[Abstract/Free Full Text]

6 Gaido KW, Maness SC, McDonnell DP, Dehal SS, Kupfer D, Safe S. Interaction of methoxychlor and related compounds with estrogen receptor alpha and beta, and androgen receptor: structure-activity studies. Mol Pharmacol 2000;58:852–8.[Abstract/Free Full Text]

7 Pike AC, Brzozowski AM, Hubbard RE. A structural biologist's view of the oestrogen receptor. J Steroid Biochem Mol Biol 2000;74:261–8.[Medline]


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