TOXICOLOGICAL HIGHLIGHT |
Corticosteroidogenesis and StAR Protein of Rainbow Trout Disrupted by Human-Use Pharmaceuticals: Data for Use in Risk Assessment
Department of Biological Sciences, Water Institute for Semi-Arid Ecosystems, University of Lethbridge, Lethbridge, Alberta, Canada T1K 3M4
1 For correspondence via Fax: (403) 329-2082. E-mail: alice.hontela{at}uleth.ca.
Received June 23, 2006; accepted June 26, 2006
Recent reports of presence of pharmaceutical drugs in surface waters (Kolpin et al., 2002
; Metcalfe et al., 2004; Miao et al., 2002) raised concerns about the potential effects of these chemicals in nontarget species, especially those in the aquatic environment (Trudeau et al., 2005). The study highlighted in this issue, "Salicylate disrupts interrenal steroidogenesis and brain glucocorticoid receptor expression in rainbow trout" by Gravel and Vijayan (2006), demonstrated, using state-of-the-art molecular tools in a well-characterized physiological model relevant for environmental toxicology, the disruption of corticosteroidogenesis by acetaminophen, ibuprofen, and salicylic acid, three human-use pharmaceuticals often detected in surface waters.
Pharmaceuticals, substances designed to exert specific physiological effects to prevent, cure, or alleviate symptoms of disease, include drugs, antibiotics, hormones, and veterinary feed additives. This new class of environmental pollutants differs from other pollutants such as endocrine-disrupting chemicals, which only incidentally interfere with normal function of nontarget species. Pharmaceuticals usually have a high therapeutic index, eliciting their desired effects in the target species (humans, livestock, or pets) at very low concentrations, with low or no toxicity. The target species are vertebrates sharing many of the basic biochemical and cellular structures with the numerous nontarget species, other vertebrates including fish (Mommsen and Moon, 2005; Norris and Carr, 2006). Fate and sources of some pharmaceuticals are already known: many are released from sewage treatment plants, landfills, or agricultural lands amended with manure and biosolids into lakes, rivers, and streams, where they are detected with high-precision analytical methods (Boxall et al., 2004; Metcalfe et al., 2004). As our analytical capabilities improve and the loading of surface waters potentially augments with changing demographics of the human population and as livestock industries expand to supply our needs, risk assessments for these new pollutants are required (Sanderson et al., 2004). We will have to determine if pharmaceuticals detected in receiving waters do pose a health risk to nontarget aquatic species and by extension to other organisms, including humans, that may be subjected to uncontrolled exposures through drinking water. There is an urgent need for studies designed to elucidate the mode of action of pharmaceuticals in nontarget species and to set safe exposure guidelines. The article by Gravel and Vijayan (2006) is an excellent example of a study that provides data regarding the mechanism of action and effects of pharmaceuticals in an environmentally relevant model species, the rainbow trout.
The researchers executed a study to determine the impacts of acetaminophen (nonsteroidal anti-inflammatory drug), ibuprofen, and salicylic acid (analgesic/antipyretic) in rainbow trout and test the hypothesis that these pharmaceuticals disrupt steroidogenesis in fish interrenal tissue, an organ homologous to the adrenal gland of mammals. The three test pharmaceuticals are highly relevant to the issue of environmental contamination by pharmaceuticals since they are extensively used by humans and they are detected in surface waters (Metcalfe et al., 2004). Exposure of the interrenal cells to the test chemicals in vitro depressed the capacity of the steroidogenic cells to synthesize cortisol in response to adrenocorticotropic hormone (ACTH). To validate the in vitro results by whole-animal exposure studies and to identify the intracellular site where the pharmaceuticals may exert their action, the researchers fed fish food laced with one of the test chemicals, salicylic acid, and assessed the transcript levels of key proteins involved in steroidogenesis of cortisol, the steroidogenic acute regulatory (StAR) protein, peripheral-type benzodiazepine receptor (PBR), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), and 11ß-hydroxylase. Again, ACTH-stimulated cortisol secretion was depressed in salicylate-treated fish, along with a lower gene expression of StAR and PBR, but not P450scc and 11ß-hydroxylase. An effect of salicylate on brain glucocorticoid receptor was also detected. The study provided, through an elegant use of physiology, molecular biology, and toxicology, evidence for significant adverse effects of three drugs designed for use in humans to control inflammation, fever, and pain, on the endocrine system of fish. Cortisol is a key steroid in these vertebrates, having a role in metabolism, as it does in mammals, as well as in osmoregulation, similar to mammalian aldosterone (Hontela, 2005; Norris and Carr, 2006). The data provided by this study, that human-use pharmaceuticals have significant hormonal effects in fish, are important since this type of mechanistic data regarding the effects of the drugs tested can be used in risk assessment.
The use of rainbow trout, a teleost fish species, by Gravel and Vijayan (2006) as the biological model in their investigation of the effects of pharmaceuticals is highly relevant to the issue of environmental impacts of these chemicals in the aquatic environment. The study is the culmination of many previous investigations carried out in the laboratory of the senior author, to characterize and increase the understanding of the teleost physiological and endocrine systems and their vulnerability to environmental pollutants. As anthropogenic pressures on the aquatic environments intensify, we need to assess the health status of the very species potentially exposed in those environments. From the classical studies relying on rats and mice for generating toxicological data, our range of model systems must now include other organisms, including fish. To detect an abnormality and relevant effects in impacted animals, we require reference data on their biology, biochemistry, and molecular constituents, data provided by comparative physiologists and biochemists (Mommsen and Moon, 2005; Norris and Carr, 2006). Vijayan's laboratory has made over the last few years a significant contribution to increase our knowledge regarding the basic physiology of cortisol in fish, the constituents of the steroidogenic pathways leading to cortisol, the impacts of environmental pollutants on this system (Vijayan et al., 2005), and, recently, the molecular markers, including StAR protein, used in the highlighted study.
The evidence that rainbow trout StAR protein is an intracellular target of the test pharmaceuticals is one of the key findings of the highlighted study. Douglas Stocco and his colleagues have previously investigated the sensitivity of StAR to a series of chemicals in mouse steroidogenic systems. Several pesticides, including lindane, dimethoate, and Roundup, (Walsh et al., 2000) depressed transcription of StAR in the testis, suppressing the synthesis of sex steroids. Taken together, the work of Viayan's and Stocco's laboratories provides strong evidence that StAR protein may be a sensitive target of many environmental pollutants, ranging from pesticides to pharmaceuticals. The consistency of a toxicological response, across species and across chemicals, is one of the elements used to establish cause-effect relationships in the evaluation of evidence in risk assessment (Sanderson et al., 2004). Impairment of StAR protein and the resulting depression of steroid synthesis may be used as a sensitive marker of potential adverse effects on reproductive fitness if gonadal StAR protein is impacted and on metabolic or osmoregulatory status if corticosteroids are impacted.
The highlighted study makes several important contributions to toxicology. First, it does provide new data on the mechanisms through which ibuprofen, acetaminophen, and salicylic acid, chemicals designed to have specific (anti-inflammatory, antipyretic, and analgesic) effects in human, impair the synthesis of a key steroid, cortisol in a nontarget species, the rainbow trout. It is an excellent example of a mechanistic toxicological study. Second, the study illustrates the power of a multidisciplinary approach, relying on comparative physiology, biochemistry, molecular biology, and toxicology, to provide relevant data for use in risk assessment of this new type of pollutants. Third, it identified the StAR protein as a vulnerable target to environmental pollutants in fish, providing support to the hypothesis that the disruption of the steroidogenic pathways is mediated through effects on this protein.
REFERENCES
Boxall, A. B. A., Fogg, L. A., Blackwell, P. A., Kay, P., Pemberton, E. J., and Croxford, A. (2004). Veterinary medicines in the environment. Rev. Environ. Contam. Toxicol. 180, 1–91.[CrossRef][Web of Science][Medline]
Gravel, A., and Vijayan, M. M. (2006). Salicylate disrupts interrenal steroidogenesis and brain glycocorticoid receptor expression in rainbow trout. Toxicol. Sci. 93, 41–49.
Hontela, A. (2005). Adrenal toxicology: Environmental pollutants and the HPI axis. In Biochemistry and Molecular Biology of Fishes, Volume 6, Environmental Toxicology (T. P. Mommsen and T. W. Moon, Eds.), pp. 331–363: chap12, Elsevier B. V., Amsterdam, Netherlands.
Kolpin, D. W., Furlong, E. T., Meyer, M., Thurman, E. M., Zaugg, S. D., Barber, L. B., and Buxton, H. T. (2002). Pharmaceuticals, hormones, and other organic wastewater contaminants in US streams, 1999–2000: A national reconnaissance. Environ. Sci. Technol. 36, 1202–1211.[Medline]
Metcalfe, C. D., Miao, X.-S., Hua, W., Letcher, R., and Servos, M. (2004). Pharmaceuticals in the Canadian environment. In Pharmaceuticals in the Environment: Sources, Fate, Effects and Risks, 2nd ed. (K. Kümmerer, Ed.), pp. 67–87. Springer-Verlag, Berlin.
Miao, X.-S., Koenig, B. G., and Metcalfe, C. D. (2002). Analysis of acidic pharmaceutical drugs in the aquatic environment using liquid chromatography-electrospray tandem mass spectrometry. J. Chromatogr. A 95, 139–147.
Mommsen, T. P., and Moon, T. W., Eds. (2005). Biochemistry and Molecular Biology of Fishes, Volume 6, Environmental Toxicology, 562 pp. Elsevier B. V., Amsterdam, Netherlands.
Norris, D. O., and Carr, J. A. (2006). Endocrine Disruptors: Biological Basis for Health Effects in Wildlife and Humans, 477 pp. Oxford University Press, New York.
Sanderson, H., Johnson, D. J., Reitsma, T., Brain, R. A., Wilson, C. J., and Solomon, K. R. (2004). Ranking and prioritization of environmental risks of pharmaceuticals in surface waters. Regul. Toxicol. Pharmacol. 39, 158–183.[CrossRef][Web of Science][Medline]
Trudeau, V. L., Metcalfe, C. D., Mimeault, C., and Moon, T. W. (2005). Pharmaceuticals in the environment: Drugged fish? In Biochemistry and Molecular Biology of Fishes, Volume 6, Environmental Toxicology (T. P. Mommsen and T. W. Moon, Eds.), pp. 475–494, Elsevier B. V., Amsterdam, Netherlands.
Vijayan, M. M., Prunet, P., and Boone, A. N. (2005). Xenobiotic impact on corticosteroid signaling. In Biochemistry and Molecular Biology of Fishes, Volume 6, Environmental Toxicology (T. P. Mommsen and T. W. Moon, Eds.), pp. 365–396.
Walsh, L. P., McCormick, C., Martin, C., and Stocco, D. M. (2000). Roundup inhibits steroidogenesis by disrupting steroidogenic acute regulatory (StAR) protein expression. Environ. Health Perspect. 108, 769–776.
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