Page 490 - The Toxicology of Fishes

470 The Toxicology of Fishes

Toxicant A
receptor
Mimics Hormone
Response
activated
Hormone Receptor

Hormone

Toxicant B
receptor
Blocks Hormone
Response
Hormone Receptor
not activated
(can be overcome with excess hormone)
FIGURE 10.4 Possible consequences of competitive binding of a toxicant to a hormone receptor. Binding of toxicant A
causes activation of the receptor, mimicking the hormone action (agonist). Binding of toxicant B does not activate the receptor
or causes weak activation, resulting in either no hormonal response or blocking hormone action when the hormone is present
(antagonist). Increasing the hormone concentrations will displace some or all of the toxicant from the binding site, thereby
reducing its antagonistic action. (Adapted from McLachlan, J.A., Environ. Health Perspect., 101, 386–388, 1993.)

–4
–3
affinities for teleost ERs 10 to 10 times lower than that of the natural ligand 17β-estradiol, similar
to the relative binding affinities for mammalian ERs (Loomis and Thomas, 1999; Nelson, 1974). Thus,
the majority of xenoestrogens are weak agonists, and their potency is due to their accumulation and
persistence in biota.
In contrast, the majority of environmental contaminants that interact with nuclear androgen and proges-
terone receptors antagonize the actions of androgens and progestins (Gray et al., 1996, 2004; Kelce et
al., 1995; Laws et al., 1995; Lundolm, 1991). Chemicals with antiandrogenic activities mediated via the
nuclear AR in mammals include para,para derivatives of DDE and DDT, the dicarboximide fungicides
vinclozolin and procymidine and their metabolites, the conazole fungicide prochloraz, and the polybro-
minated biphenyl mixtures DE-71 and DE-100 (Gray et al., 2004). Phthalate esters, which possess some
antiandrogenic properties, do not bind to the nuclear AR. Recently, chemicals with androgenic activities
that bind to the nuclear AR and cause masculinization of fish have been detected in pulp and paper mill
effluents and in feedlot effluents (Gray et al., 2004; Jenkins et al., 2000; Larsson and Forlin, 2002; Larsson
et al., 2006; Orlando et al., 2003; Parks et al., 2001). Masculinization effects observed include the
development of a gonopodium in female mosquitofish and the development of nuptial tubercles and
reduced vitellogenin levels in female fathead minnow (Ankley et al., 2003; Howell et al., 1980).
The androgenic chemicals in these effluents have not been identified to date, although trenbolone, the
anabolic steroid administered to domestic animals, or an active metabolite is a likely candidate for a
potent androgen in feedlot effluents. Trenbolone has recently been shown to have androgenic effects in
the fathead minnow, causing the development of nuptial tubercles in females, an effect blocked by co-
administration of the nuclear androgen receptor antagonist flutamide (Ankley et al., 2004). In contrast,
metabolites of the fungicide vinclozolin, which are competitors for androgen binding to fish androgen
receptors (Sperry and Thomas, 1999) and have antiandrogenic activities, have been shown to downreg-
ulate the activity of the aromatase enzyme in fathead minnow (Ankley et al., 2005) and therefore have
the potential to impair both androgenic and estrogenic actions in fish. In conclusion, extensive evidence
suggests that a broad range of contaminants that influence the endocrine system are present in sufficient
concentrations in many polluted environments to alter genomic steroid action mediated by nuclear
estrogen, androgen, and progesterone receptors. Factors that affect the degree of endocrine disruption
by this mechanism are discussed in the following section, and evidence for its occurrence in natural
populations of fish inhabiting polluted waters is reviewed in later chapters.