Other Hormone Axes and Possible Levels of Disruption

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There are other hormone axes similar in structure to the reproductive axis. These include the growth, thyroid, and stress axes (Fig. 3). The proper biological function of each axis depends on the concentration of hormones, whose control, production, availability, and action are similar to the reproductive axis. Because of these structural parallels, each of these endocrine axes has the potential for modulation by xenobiotics [102, 103]. Few studies have been designed to examine the possible effects of xenobiotics on these other axes. It is important that we examine these possible direct effects as well as the indirect effects that could occur through cross talk or interaction between axes.

As an example, the stress axis is known to affect the reproductive and growth axes in fish. Increases in stress hormones are associated with impaired reproductive function and decreases in growth rate [39]. There is still a great deal of research needed to understand the normal endocrine mechanisms involved in these relationships. Recently, glucocorticoid receptors were immunolocalized in the neurons in the part of the brain associated with the control of reproduction and the pituitary of rainbow trout (Oncorhynchus mykiss) [104]. This research suggests a mechanistic connection between stress hormones and the brain-level control of reproductive steroid hormones. A few studies have examined the modulation of the stress axis in fish by xenobiotics such as paper mill effluent and PCBs and heavy metals [54,55,105]. Even fewer studies have been implemented to look at the possible effects of the stress response on reproductive steroid hormones of contaminant-exposed fish [54]. Given the presence of the glucocorti-coid receptor in the brain and pituitary of certain fish, it is important that we examine the role of xenobiotics as stressors in the modulation of reproduction.

As members of the nuclear superfamily, reproductive and stress steroid hormone receptors belong to a group of hormones that include thyroid hormones, retinoic acid, and vitamin D3 [106]. In the past, these hormones were believed to act strictly as intranuclear transcription regulators. Recent studies have found the existence of membrane bound receptors for estrogens in fish and mammals [32,33,107]. Membrane bound receptors would add another function to the steroid hormone and possibly other members of the nuclear superfamily. In addition to their role as transcription regulators, estrogens acting through membrane receptors and secondary messenger systems could mediate cell activity (enzyme activation/inhibition and intracellular ion concentration) (Fig. 2). Future research should examine steroid membrane receptor nonge-nomic function alone or perhaps in conjunction with nuclear receptors of native hormones and xenobiotics.

Among the nuclear receptor superfamily there are receptors with unidentified ligands (hormones) called orphan receptors [108]. Some of these orphan receptors are now receiving names as their ligands are discovered. For example, the steroid-xenobiotic receptor (SXR) is a nuclear receptor that has been shown to activate transcription when bound by certain native steroid hormones or xenobiotics. SXR appears to induce transcription of xenobiotic and steroid hormone detoxification and metabolizing enzymes [37]. Steroidogenic factor-1 (SF-1) is still an orphan receptor because its ligand remains unidentified. However, it has been associated with regulation of some P450 steroidogenic enzymes, and more recently was shown to play an important role in the development of the gonad and adrenal glands in mice [109] and gonadal sex-differentiation in the chicken [110]. The obvious influence of former and present orphan receptors on development and reproduction in lab animals strongly suggests that more research is required into the relationship of xenobiotics with these receptors. One has to be curious about what future research will uncover concerning the roles of the remaining orphan receptors.

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