Adverse outcome pathway (AOP) networks potentially provide a basis for predictive approaches to assess the toxicity of chemical mixtures. This study evaluated the utility of a simple AOP network to predict the interactive effects of a binary chemical mixture comprised of an inhibitor of the aromatase enzyme (fadrozole, a human pharmaceutical) and an agonist of the androgen receptor (trenbolone, a veterinary drug). Overall, prediction of interactive effects of the two chemicals based on the AOP network did not match actual observed effects. Rather, the two compounds seemed to interact in an independent manner in terms of their effects on the hypothalamic-pituitary-gonadal axis in the fish. This dataset is associated with the following publication: Ankley, G., B. Blackwell, J. Cavallin, J. Doering, D.J. Feifarek, K. Jensen, M. Kahl, C. Lalone, S. Poole, E. Randolph, T. Saari, and D. Villeneuve. Adverse outcome pathway network-based assessment of the interactive effects of an androgen receptor agonist and an aromatase inhibitor on fish endocrine function. AQUATIC TOXICOLOGY. Elsevier Science Ltd, New York, NY, USA, 39(4): 913-922, (2020).

This research was designed to evaluate whether a biologically-based computational model aligned with an adverse outcome pathway (AOP) could effectively predict animal (in vivo) responses to chemicals shown to inhibit the enzyme aromatase in a non-animal (in vitro) screening assays. Aromatase is an enzyme that plays a critical role in the synthesis of estrogens, an important class of hormones, and chemicals that inhibit aromatase are viewed as probable endocrine disrupting compounds. Although the model was not able to accurately predict the average in vivo responses observed for all chemicals tested, there was strong qualitative to semi-quantitative agreement with the proposed AOP and predictions did fall within the distribution of measured values. Consequently, this “new approach methodology” likely has utility for screening-level assessments. This work helps to establish the confidence and limitations of this approach. The data set includes: 1) High throughput screening results for chemicals identified as aromatase inhibitors. 2) Novel in vitro aromatase inhibition data for six chemicals. 3) Modeled predictions of impacts on 17b-estradiol and vitellogenin concentrations over a range of concentrations. 4) Measured biological effects of 3 aromatase inhibitors in fathead minnows exposed for 24 h. 5) Measured plasma and water concentrations of the test chemicals. This dataset is associated with the following publication: Villeneuve, D., B. Blackwell, J. Cavallin, W. Cheng, R. Conolly, D. Feifarek, K. Jensen, M. Kahl, R. Milsk, S. Poole, E. Randolph, T. Saari, and G. Ankley. Case study in 21st century ecotoxicology: Using in vitro aromatase inhibition data to predict short term in vivo responses in adult female fish. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, USA, 40(4): 1155-1170, (2021).

This research was designed to evaluate whether a biologically-based computational model aligned with an adverse outcome pathway (AOP) could effectively predict animal (in vivo) responses to chemicals shown to inhibit the enzyme aromatase in a non-animal (in vitro) screening assays. Aromatase is an enzyme that plays a critical role in the synthesis of estrogens, an important class of hormones, and chemicals that inhibit aromatase are viewed as probable endocrine disrupting compounds. Although the model was not able to accurately predict the average in vivo responses observed for all chemicals tested, there was strong qualitative to semi-quantitative agreement with the proposed AOP and predictions did fall within the distribution of measured values. Consequently, this “new approach methodology” likely has utility for screening-level assessments. This work helps to establish the confidence and limitations of this approach. The data set includes: 1) High throughput screening results for chemicals identified as aromatase inhibitors. 2) Novel in vitro aromatase inhibition data for six chemicals. 3) Modeled predictions of impacts on 17b-estradiol and vitellogenin concentrations over a range of concentrations. 4) Measured biological effects of 3 aromatase inhibitors in fathead minnows exposed for 24 h. 5) Measured plasma and water concentrations of the test chemicals. This dataset is associated with the following publication: Villeneuve, D., B. Blackwell, J. Cavallin, W. Cheng, R. Conolly, D. Feifarek, K. Jensen, M. Kahl, R. Milsk, S. Poole, E. Randolph, T. Saari, and G. Ankley. Case study in 21st century ecotoxicology: Using in vitro aromatase inhibition data to predict short term in vivo responses in adult female fish. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, USA, 40(4): 1155-1170, (2021).

Data set includes empirical results from 60 h, 10 d, and 21 d exposures of female fathead minnows to the fungicide imazalil as well as simulations from predictive models anchored to an established adverse outcome pathway (https://aopwiki.org/aops/25). Contents are organized into multiple tabs: (1) Simulated effects on plasma 17b-estradiol and vitellogenin used to inform experimental design. (2) Model simulations based on nominal concentrations used in the 60 h, 10 d, and 21 d exposures. (3) Biological effects data from the 60 h experiment. (4) Analytical exposure verification from the 60 h experiment. (5) Biological effects data from the 10 d exposure. (6) Biological effects data from 21 d exposure. (7) Analytical exposure verification from the 10 d and 21 d exposures. (8) Reproduction data from the 10 d and 21 d exposures. (9) Simulated reproduction results based on nominal exposure concentrations used in the 10 d and 21 d exposures. (10) Histopathology evaluations for selected females from the 10 d and 21 d exposures. This dataset is associated with the following publication: Villeneuve, D., B. Blackwell, C. Blanksma, J. Cavallin, W. Cheng, R. Conolly, K. Conrow, D. Feifarek, L. Heinis, K. Jensen, M. Kahl, R. Milsk, S. Poole, E. Randolph, T. Saari, K. Watanabe, and G. Ankley. Case Study in 21st-Century Ecotoxicology: Using In Vitro Aromatase Inhibition Data to Predict Reproductive Outcomes in Fish In Vivo. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, USA, 42(1): 100-116, (2023).

Data set includes empirical results from 60 h, 10 d, and 21 d exposures of female fathead minnows to the fungicide imazalil as well as simulations from predictive models anchored to an established adverse outcome pathway (https://aopwiki.org/aops/25). Contents are organized into multiple tabs: (1) Simulated effects on plasma 17b-estradiol and vitellogenin used to inform experimental design. (2) Model simulations based on nominal concentrations used in the 60 h, 10 d, and 21 d exposures. (3) Biological effects data from the 60 h experiment. (4) Analytical exposure verification from the 60 h experiment. (5) Biological effects data from the 10 d exposure. (6) Biological effects data from 21 d exposure. (7) Analytical exposure verification from the 10 d and 21 d exposures. (8) Reproduction data from the 10 d and 21 d exposures. (9) Simulated reproduction results based on nominal exposure concentrations used in the 10 d and 21 d exposures. (10) Histopathology evaluations for selected females from the 10 d and 21 d exposures. This dataset is associated with the following publication: Villeneuve, D., B. Blackwell, C. Blanksma, J. Cavallin, W. Cheng, R. Conolly, K. Conrow, D. Feifarek, L. Heinis, K. Jensen, M. Kahl, R. Milsk, S. Poole, E. Randolph, T. Saari, K. Watanabe, and G. Ankley. Case Study in 21st-Century Ecotoxicology: Using In Vitro Aromatase Inhibition Data to Predict Reproductive Outcomes in Fish In Vivo. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, USA, 42(1): 100-116, (2023).

"Morshead ML, Jensen KM, Ankley GT, Vliet S, LaLone CA, Aller AV, Watanabe KH, Villeneuve DL. Putative adverse outcome pathway development based on physiological responses of female fathead minnows to model estrogen versus androgen receptor agonists. Aquat Toxicol. 2023 Aug;261:106607. doi: 10.1016/j.aquatox.2023.106607. Epub 2023 Jun 9. PMID: 37354817.". This dataset is associated with the following publication: Morshead, M., K. Jensen, G. Ankley, S. Vliet, C. LaLone, D. Villeneuve, A. Vidales Aller, and K. Watanabe. Putative adverse outcome pathway development based on physiological responses of female fathead minnows to model estrogen versus androgen receptor agonists. AQUATIC TOXICOLOGY. Elsevier Science Ltd, New York, NY, USA, 261: 106607, (2023).

There is significant concern regarding potential impairment of fish reproduction associated with endocrine disrupting chemicals. Aromatase (CYP19) is a steroidogenic enzyme involved in the conversion of androgens to estrogens. Inhibition of aromatase by chemicals can result in reduced concentrations of estrogens leading to adverse reproductive effects. These effects have been extensively investigated in a small number of laboratory model fishes, but differences in sensitivity among species is largely unknown. Therefore, this study took a first step towards understanding potential differences in sensitivity to aromatase inhibitors among fishes. Specifically, a standard in vitro aromatase inhibition assay using subcellular fractions of whole tissue homogenates was used to evaluate the potential sensitivity of eighteen phylogenetically diverse species of freshwater fish to the nonsteroidal aromatase inhibitor fadrozole. Sensitivity to fadrozole ranged by more than 52-fold among these species. Five species were further investigated for sensitivity to up to four additional nonsteroidal aromatase inhibitors, letrozole, imazalil, prochloraz, and propiconazole. Potencies of each of these chemicals relative to fadrozole ranged by up to two orders of magnitude among the five species. Commonly investigated laboratory model species were among the least sensitive to all the investigated chemicals; therefore, ecological risks of aromatase inhibitors derived from these species might not be adequately protective of more sensitive native fishes. This information could guide more objective ecological risk assessments of native fishes to chemicals that inhibit aromatase. This dataset is associated with the following publication: Doering, J., D. Villeneuve, K. Fay, E. Randolph, K. Jensen, M. Kahl, C. LaLone, and G. Ankley. Differential sensitivity to in vitro inhibition of cytochrome P450 aromatase (CYP19) activity among 18 freshwater fishes. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 170(2): 394-403, (2019).

There is significant concern regarding potential impairment of fish reproduction associated with endocrine disrupting chemicals. Aromatase (CYP19) is a steroidogenic enzyme involved in the conversion of androgens to estrogens. Inhibition of aromatase by chemicals can result in reduced concentrations of estrogens leading to adverse reproductive effects. These effects have been extensively investigated in a small number of laboratory model fishes, but differences in sensitivity among species is largely unknown. Therefore, this study took a first step towards understanding potential differences in sensitivity to aromatase inhibitors among fishes. Specifically, a standard in vitro aromatase inhibition assay using subcellular fractions of whole tissue homogenates was used to evaluate the potential sensitivity of eighteen phylogenetically diverse species of freshwater fish to the nonsteroidal aromatase inhibitor fadrozole. Sensitivity to fadrozole ranged by more than 52-fold among these species. Five species were further investigated for sensitivity to up to four additional nonsteroidal aromatase inhibitors, letrozole, imazalil, prochloraz, and propiconazole. Potencies of each of these chemicals relative to fadrozole ranged by up to two orders of magnitude among the five species. Commonly investigated laboratory model species were among the least sensitive to all the investigated chemicals; therefore, ecological risks of aromatase inhibitors derived from these species might not be adequately protective of more sensitive native fishes. This information could guide more objective ecological risk assessments of native fishes to chemicals that inhibit aromatase. This dataset is associated with the following publication: Doering, J., D. Villeneuve, K. Fay, E. Randolph, K. Jensen, M. Kahl, C. LaLone, and G. Ankley. Differential sensitivity to in vitro inhibition of cytochrome P450 aromatase (CYP19) activity among 18 freshwater fishes. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 170(2): 394-403, (2019).

A collection of R scripts useful for extracting and analyzing adverse outcome pathway network data from the adverse outcome pathway wiki (aopwiki.org). This dataset is associated with the following publication: Pollesch, N., D. Villeneuve, and J. O'Brien. Extracting and benchmarking emerging adverse outcome pathway knowledge. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 168(2): 349-364, (2019).

A collection of R scripts useful for extracting and analyzing adverse outcome pathway network data from the adverse outcome pathway wiki (aopwiki.org). This dataset is associated with the following publication: Pollesch, N., D. Villeneuve, and J. O'Brien. Extracting and benchmarking emerging adverse outcome pathway knowledge. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 168(2): 349-364, (2019).