Predicting the Relative Sensitivity of Sturgeons to Aryl Hydrocarbon Receptor Agonists

Along with overexploitation and habitat loss, pollution is one cause for decreases in populations of fishes. One class of pollutants of particular global environmental concern to fishes are dioxin-like compounds (DLCs). DLCs elicit their toxicity through activation of the aryl hydrocarbon receptor (AHR). Despite this common mechanism of all DLCs, dramatic differences in sensitivity exist among fishes. Sturgeons (Acipenseridae) are an ancient family of fishes in which most species are endangered. It is hypothesized that pollutants, including DLCs, might be contributing to the observed declines in populations because sturgeons have a unique life-style that makes them susceptible to exposure to bioaccumulative chemicals. However, determining sensitivities of sturgeons to DLCs through traditional in vivo toxicity testing is not feasible for practical and ethical reasons. Therefore, the aim of this research was to develop a mechanism-based biological model capable of predicting the relative sensitivity of sturgeons to DLCs. This mechanism-based biological model was developed through investigations into the AHR and AHR-mediated molecular and biochemical responses of white sturgeon (Acipenser transmontanus) relative to teleost fishes and another species of sturgeon. White sturgeon responded to activation of the AHR in a manner that is consistent with responses of teleost fishes (induction of cytochrome P450 1A). Two AHRs with similar levels of expression were identified in white sturgeon, an AHR1 that resembles AHR1s of tetrapods and an AHR2 that resembles AHR2s of other fishes. Both AHR1 and AHR2 of white sturgeon were activated by exposure to five selected DLCs in vitro with effect concentrations less than any other AHR tested to date. These findings were suggestive that white sturgeon might be among the most sensitive species of fish to exposure to DLCs. These findings raised the question as to whether other members of the Acipenseridae are similarly sensitive to exposure to DLCs. Therefore, AHR1 and AHR2 were identified in a second species of sturgeon, the lake sturgeon (Acipenser fulvescens). AHR1 of lake sturgeon had the same in vitro sensitivity to activation by the five selected DLCs as AHR1 of white sturgeon, while AHR2 of lake sturgeon was 10-fold less sensitive to activation by the five selected DLCs relative to AHR2 of white sturgeon. AHR2 has been demonstrated to drive adverse effects of DLCs in other fishes, while AHR1 has no known role in mediating toxicities in fishes. Therefore, it was hypothesized that white sturgeon are 10-fold more sensitive to DLCs relative to lake sturgeon in vivo. However, there were uncertainties in whether differences in activation of the AHR are representative of differences at higher levels of biological organization. Therefore, whole transcriptome and whole proteome responses were investigated following exposure to equipotent concentrations of three agonists of the AHR. Equal activation of the AHR of white sturgeon resulted in similar global responses and magnitude of responses across levels of biological organization. This supports the hypothesis that activation of the AHR is predictive of apical level adverse effects of regulatory relevance, such as mortality of embryos. In order to test this hypothesis, AHR1s and AHR2s from seven species of fish of known sensitivity were investigated and the relationship between in vitro and in vivo sensitivities were characterized for the model DLC, 2,3,7,8-TCDD. All AHR1s and AHR2s were activated in vitro by 2,3,7,8-TCDD. There was no significant linear relationship between in vitro sensitivity of AHR1 and in vivo sensitivity among the seven species. However, there was a highly significant linear relationship between in vitro sensitivity of the AHR2 and in vivo sensitivity. The equation of this relationship enables the prediction of the in vivo sensitivity of any species of fish based on in vitro sensitivity of the AHR2. This predictive model could be essential in guiding more objective risk assessments of DLCs to fishes, including endangered species such as sturgeons.

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