Endocrine Disrupting Chemicals

Many compounds introduced into the environment by human activity have been implicated in endocrine disruption. Because of the diversity of structure and mechanism of action of these compounds, and as yet uncertain synergistic effects of mixtures, the development of management strategies (e.g. by environmental agencies and legislators) has been difficult. Compounds implicated are often ubiquitous and persistent, and may bioaccumulate at chronically polluted sites. For instance, the bioaccumulation concentration factor (BCF) for DDT in aquatic animals5 ranges from 25 000 to 100000 whilst that of nonylphenol approaches 300.6 The duration and timing of exposure are also important. Short term exposure of the echinoderm Asterias rubens to 200ugl^ of cadmium caused a reduction in ovary growth. Long term exposure to 25 ugl^ caused a delay in ovarian growth which was obvious after 5 months exposure but by the end of the reproductive cycle the difference had become smaller.7 Some of the many compounds implicated in endocrine disruption are shown in Table 1.8

The difficulty of predicting the endocrine disruptive potential of any chemical is illustrated by the diverse variety of structures that possess estrogenic activity. Naturally occurring estrogens, such as 17^-estradiol, are 18-carbon steroids with a phenolic a ring and a ^-hydroxy group or ketone at position 17 of the % ring (Figure 1). The conformation of the estrogen receptor contains a binding pocket into which the phenolic ring fits. The structure of the remainder of the molecule then determines the affinity of binding and the mode of action as an agonist or antagonist, depending on its ability to allow the correct conformational changes by the receptor.9 Yet while most xenoestrogens showing high receptor affinity possess a para-substituted phenolic ring/0 some have more than one (methoxychlor metabolites and diphenolic isoflavonoids) and others have none (chlordecone and o,p'-DDT). Structural rigidity imparted by conformational restriction may explain the ability of compounds such as para-substituted hydroxylated metabolites of PCBs to bind the estrogen receptor," and explain the fact that the o,p'-isomer of DDT is estrogenic while the p,p'-isomer is only weakly estrogenic. i2

The QSAR (quantitative structure-activity relationship) approach has been considered for the identification of toxicants that bind to steroid and aryl

5 A. C. Nimrod and W.H. Benson, Crit. Rev. Toxicol, 1996, 26, 335.

6 R. Ekelund, A. Bergman, A. Granno and M. Berggren, Environ. Pollut., 1990, 64, 107.

7 P.J. Den Besten, J.R. Maas, D.R. Livingstone, D.I. Zandee and P.A. Voot, Comp. Biochem. Physiol. C, 1991, 100, 165.

8 L. E. Gray Jr., E. Monosson and W. R. Kelce in Interconnections between Human and Ecosystem Health, ed. E. Monosson and R. T. Di Giulio, Chapman and Hall, London, pp. 45-82.

9 W.L. Daux and J.F. Griffin, J. Steroid Biochem., 1987, 27, 271.

10 V. C. Jordan, S. Mittal, B. Gosden, R. Koch and M. E. Lieberman, Environ. Health Perspect., 1985, 61, 97.

11 J.D. McKinney and C.L. Waller, Environ. Health Perspect, 1994, 102, 290.

12 D. Kupferand D.H. Bulger, Estrogenic Properties of DDT and Its Analogues, in Estrogens in the Environment, ed. J.A. McLachlan, Elsevier, New York, 1980, p. 239.

Table 1 Examples of chemicals suspected of causing endocrine disruption listed according to suspected mechanism of action

Environmental estrogens: estrogen receptor mediated Chlordecone

Polychlorinated biphenyls (PCBs) o,p'-DDT

Environmental antiestrogens Dioxin p,p'-DDT/DDE Endosulfan

Environmental antiandrogens Vinclozolin Procymidone Kraft mill effluent

Toxicants that alter circulating steroid hormone levels

Dioxin

Endosulfan

Aroclor 1254

Toxicants that act via the CNS Dithiocarbamate pesticides Carbon disulfide Manganese

Other mechanisms Dibutyl phthalate Benzidine-based dyes Vinylcyclohexene

Antithyroid endocrine disruptors PCBs

Herbicides, e.g. nitrofen Phthalic acid esters

Adrenal endocrine disruptors Aniline dyes Ketoconazole fungicides PCBs

Adapted from Gray et al.s hydrocarbon (Ah) receptors.13 This procedure is limited by the extent of information available to form a reliable database. The promiscuous nature of estrogen and other steroid binding sites within the steroid receptor superfamily, and the level of interspecies variability, also complicate the issue.

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