Mechanisms of Action

Surprisingly little is also known about the mechanisms of action of many (perhaps most) EDCs. Some are certainly oestrogenic, and much attention has been focused on these chemicals, primarily because some of the best-documented examples of endocrine disruption in wildlife (e.g. the 'feminisation' of male alligators in the US [3] and fish in the UK [2]) appear to be due to exposure to oestro-genic chemicals. Further, the wide availability of in vitro assays for oestrogens has meant that it is relatively easy to screen chemicals for oestrogenic activity. Such screening has demonstrated that a surprisingly diverse range of chemicals, such as some alkylphenols, phthalates, bi-phenolic chemicals and pesticides, all of which are well-documented aquatic pollutants, are oestrogenic, albeit usually only weakly so (e.g. [45,60]). A relatively small proportion of these chemicals has also been shown to demonstrate oestrogenic activity in vivo; the well documented increase in the plasma vitellogenin concentration of fish in response to nonylphe-nol is probably the best example [46]. However, because a chemical demonstrates oestrogenic activity does not necessarily mean that any effects it causes in vivo are a consequence of the oestrogenic activity of the chemical. For example, p,p'-DDE is weakly oestrogenic in vitro, but shows anti-androgenic effects in vivo [61], leading to the suggestion that some of the 'oestrogenic' effects observed in wildlife are, in fact, caused by the anti-androgenic nature of some chemicals [61]. The general message that is slowly appearing is that many EDCs may well have multiple endocrine activities (i.e. a chemical could have oestrogenic and also anti-andro-genic activities [62]), and hence presumably have multiple mechanisms of action in vivo, though this has yet to be demonstrated (and will be difficult).

Besides interacting directly (as agonists or antagonists) with steroid hormone receptors, and thus influencing the rates of transcription of the many genes regulated by steroid hormones, many EDCs probably also exert more indirect effects on reproduction. For example, it is likely that many of the enzymes involved in the biosynthesis of steroid hormones are themselves affected by EDCs. These effects could include altering the rates of expression of the genes coding for the enzymes (and hence affecting the levels of the enzymes), and acting as surrogate substrates for these enzymes (if chemicals with endocrine activity can mimic the structures of natural sex steroids, then they can presumably also act as substrates for enzymes that play roles in the biosynthesis of steroids).Although there are limited data available presently to support my contention that EDCs will have multiple mechanisms of action, especially in vivo, it has already been shown that nonylphenol affects a number of enzymes of the cytochrome P450-dependent monooxygenase system [63], which plays a central role in the oxidative metabolism or biotransformation of a wide range of foreign and endogenous compounds.

With so many potential mechanisms of action, it will not be an easy task to clarify exactly how a particular chemical, let alone a mixture of chemicals, causes a particular effect, or suite of effects; in the case of fish exposed to very complex, ill-defined, mixtures of chemicals, it may well never be possible to be certain exactly what chemicals cause the effects, or how they do so.

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