Species extrapolation for the 21st century

Safety factors are used in ecological risk assessments to extrapolate from the toxic responses of laboratory test species to all species representing that group in the environment. More accurate extrapolation of species responses is important. Advances in understanding the mechanistic basis for toxicological responses and identifying molecular response pathways can provide a basis for extrapolation across species and, in part, an explanation for the variability in whole organism responses to toxicants. We highlight potential short- and medium-term development goals to meet our long-term aspiration of truly predictive in silico extrapolation across wildlife species' response to toxicants. A conceptual approach for considering cross-species extrapolation is presented. Critical information is required to establish evidence-based species extrapolation, including identification of critical molecular pathways and regulatory networks that are linked to the biological mode of action and species' homologies. A case study is presented that examines steroidogenesis inhibition in fish after exposure to fadrozole or prochloraz. Similar effects for each compound among fathead minnow, medaka, and zebrafish were attributed to similar inhibitor pharmacokinetic/pharmacodynamic distributions and sequences of cytochrome P45019A1/2 (CYP19A1/2). Rapid advances in homology modeling allow the prediction of interactions of chemicals with enzymes, for example, CYP19 aromatase, which would eventually allow a prediction of potential aromatase toxicity of new compounds across a range of species. Eventually, predictive models will be developed to extrapolate across species, although substantial research is still required. Knowledge gaps requiring research include defining differences in life histories (e.g., reproductive strategies), understanding tissue-specific gene expression, and defining the role of metabolism on toxic responses and how these collectively affect the power of interspecies extrapolation methods.

[1]  Martin van den Berg,et al.  A comparison of human H295R and rat R2C cell lines as in vitro screening tools for effects on aromatase. , 2004, Toxicology letters.

[2]  Thomas H Hutchinson,et al.  Ecotoxicogenomics: the challenge of integrating genomics into aquatic and terrestrial ecotoxicology. , 2004, Aquatic toxicology.

[3]  L. Browne,et al.  Fadrozole hydrochloride: a potent, selective, nonsteroidal inhibitor of aromatase for the treatment of estrogen-dependent disease. , 1991, Journal of medicinal chemistry.

[4]  H Segner,et al.  Cytochrome P4501A induction caused by the imidazole derivative Prochloraz in a rainbow trout cell line. , 2005, Toxicology in vitro : an international journal published in association with BIBRA.

[5]  Thomas Braunbeck,et al.  Description and initial evaluation of a Xenopus metamorphosis assay for detection of thyroid system‐disrupting activities of environmental compounds , 2005, Environmental toxicology and chemistry.

[6]  Masayuki Yamamoto,et al.  Intrinsic Function of the Aryl Hydrocarbon (Dioxin) Receptor as a Key Factor in Female Reproduction , 2005, Molecular and Cellular Biology.

[7]  Takanobu Mizuta,et al.  Presence of sex steroids and cytochrome P450 genes in amphioxus. , 2007, Endocrinology.

[8]  Daniel L Villeneuve,et al.  Vision & strategy: Predictive ecotoxicology in the 21st century , 2011, Environmental toxicology and chemistry.

[9]  Arthur J. Olson,et al.  AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading , 2009, J. Comput. Chem..

[10]  Maria Linderoth,et al.  Altered steroid metabolism in several teleost species exposed to endocrine disrupting substances in refuse dump leachate. , 2003, General and comparative endocrinology.

[11]  Daniel L Villeneuve,et al.  Linkage of biochemical responses to population‐level effects: A case study with vitellogenin in the fathead minnow (Pimephales promelas) , 2007, Environmental toxicology and chemistry.

[12]  Helmut Segner,et al.  Effects of prochloraz and nonylphenol diethoxylate on hepatic biotransformation enzymes in trout: a comparative in vitro/in vivo-assessment using cultured hepatocytes. , 2001, Aquatic toxicology.

[13]  Martin van den Berg,et al.  Induction and inhibition of aromatase (CYP19) activity by various classes of pesticides in H295R human adrenocortical carcinoma cells. , 2002, Toxicology and applied pharmacology.

[14]  M. Goddard,et al.  Sex enhances adaptation by unlinking beneficial from detrimental mutations in experimental yeast populations , 2012, BMC Evolutionary Biology.

[15]  Don Bradshaw,et al.  Hormonal control of salt and water balance in vertebrates. , 2006, General and comparative endocrinology.

[16]  A. Tarrant,et al.  Endocrine-like Signaling in Cnidarians: Current Understanding and Implications for Ecophysiology1 , 2005, Integrative and comparative biology.

[17]  L. Gray,et al.  Effects of two fungicides with multiple modes of action on reproductive endocrine function in the fathead minnow (Pimephales promelas). , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[18]  A. Sali,et al.  Modeling of loops in protein structures , 2000, Protein science : a publication of the Protein Society.

[19]  Thomas H Hutchinson,et al.  Reproductive and developmental effects of endocrine disrupters in invertebrates: in vitro and in vivo approaches. , 2002, Toxicology letters.

[20]  Daniel L Villeneuve,et al.  Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment , 2010, Environmental toxicology and chemistry.

[21]  S. Ekins,et al.  Evolution of pharmacologic specificity in the pregnane X receptor , 2008, BMC Evolutionary Biology.

[22]  David S. Goodsell,et al.  AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility , 2009, J. Comput. Chem..

[23]  William H. Benson,et al.  Genomic approaches for cross-species extrapolation in toxicology : proceedings from the Workshop on Emerging Molecular and Computational Approaches for Cross-Species Extrapolations, 18-22 July 2004, Portland, Oregon USA , 2006 .

[24]  Matthias Platzer,et al.  CYP3 phylogenomics: evidence for positive selection of CYP3A4 and CYP3A7 , 2008, Pharmacogenetics and genomics.

[25]  Wissem Mnif,et al.  Identification of new human pregnane X receptor ligands among pesticides using a stable reporter cell system. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[26]  Yann Guiguen,et al.  Main Neuro-Endocrine, Endocrine and Paracrine Regulations of Fish Reproduction, and Vulnerability to Xenobiotics , 2000 .

[27]  F. Guengerich.  Cytochrome p450 and chemical toxicology. , 2008, Chemical research in toxicology.

[28]  Jiang-Shiou Hwang,et al.  Hormones and reproduction in scleractinian corals. , 2006, Comparative biochemistry and physiology. Part A, Molecular & integrative physiology.

[29]  Thomas Ludwig,et al.  The AxML program family for maximum likelihood‐based phylogenetic tree inference , 2004, Concurr. Pract. Exp..

[30]  J. Lay,et al.  Development of methods for evaluating toxicity to freshwater ecosystems. , 2000, Ecotoxicology and environmental safety.

[31]  S. Ekins,et al.  In silico pharmacology for drug discovery: methods for virtual ligand screening and profiling , 2007, British journal of pharmacology.

[32]  Xiaowei Zhang,et al.  Responses of the medaka HPG axis PCR array and reproduction to prochloraz and ketoconazole. , 2008, Environmental science & technology.

[33]  A. Sali,et al.  Comparative protein structure modeling of genes and genomes. , 2000, Annual review of biophysics and biomolecular structure.

[34]  Demetrio Raldúa,et al.  First evidence of endocrine disruption in feral carp from the Ebro River. , 2004, Toxicology and applied pharmacology.

[35]  Eric D Wieben,et al.  Human aromatase: gene resequencing and functional genomics. , 2005, Cancer research.

[36]  Francesc Piferrer,et al.  Endocrine sex control strategies for the feminization of teleost fish , 2001 .

[37]  G. Callard,et al.  Identification of multiple CYP19 genes encoding different cytochrome P450 aromatase isozymes in brain and ovary. , 1998, Endocrinology.

[38]  Robert C. Edgar,et al.  MUSCLE: multiple sequence alignment with high accuracy and high throughput. , 2004, Nucleic acids research.

[39]  Y. Ito,et al.  Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. , 1994, Endocrine reviews.

[40]  J. Schlatter,et al.  Azole fungicides affect mammalian steroidogenesis by inhibiting sterol 14 alpha-demethylase and aromatase. , 2002, Environmental health perspectives.

[41]  Urban Olsson,et al.  Phylogenetic Analysis of the Cytochrome P450 3 (CYP3) Gene Family , 2003, Journal of Molecular Evolution.

[42]  S. Bradbury,et al.  Meeting the scientific needs of ecological risk assessment in a regulatory context. , 2004, Environmental science & technology.

[43]  Cheryl A Murphy,et al.  Adverse outcome pathways and ecological risk assessment: Bridging to population‐level effects , 2011, Environmental toxicology and chemistry.

[44]  A M Vinggaard,et al.  Screening of selected pesticides for inhibition of CYP19 aromatase activity in vitro. , 2000, Toxicology in vitro : an international journal published in association with BIBRA.

[45]  T. Blundell,et al.  Comparative protein modelling by satisfaction of spatial restraints. , 1993, Journal of molecular biology.

[46]  Wolfgang Völkel,et al.  Comparative Assessment of the Inhibition of Recombinant Human CYP19 (Aromatase) by Azoles Used in Agriculture and as Drugs for Humans , 2004, Endocrine research.

[47]  L Filipe C Castro,et al.  The genomic environment around the Aromatase gene: evolutionary insights , 2005, BMC Evolutionary Biology.

[48]  Xiaowei Zhang,et al.  Time‐Dependent transcriptional profiles of genes of the hypothalamic‐pituitary‐gonadal axis in medaka (Oryzias latipes) exposed to fadrozole and 17β‐trenbolone , 2008, Environmental toxicology and chemistry.

[49]  Gerald T Ankley,et al.  Evaluation of the aromatase inhibitor fadrozole in a short-term reproduction assay with the fathead minnow (Pimephales promelas). , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[50]  W. Pangborn,et al.  Structural basis for androgen specificity and oestrogen synthesis in human aromatase , 2009, Nature.

[51]  Stephen W. Edwards,et al.  Reverse engineering adverse outcome pathways , 2011, Environmental toxicology and chemistry.

[52]  Ben M. Webb,et al.  Comparative Protein Structure Modeling Using MODELLER , 2007, Current protocols in protein science.

[53]  J. Thornton,et al.  PROCHECK: a program to check the stereochemical quality of protein structures , 1993 .

[54]  J. Ian Mason,et al.  Imidazole antimycotics: Selective inhibitors of steroid aromatization and progesterone hydroxylation , 1987, Steroids.

[55]  Michael Y. Galperin,et al.  Nucleic Acids Research annual Database Issue and the NAR online Molecular Biology Database Collection in 2009 , 2008, Nucleic Acids Res..

[56]  B Testa,et al.  In silico pharmacology for drug discovery: applications to targets and beyond , 2007, British journal of pharmacology.

[57]  Sayan Mukherjee,et al.  Computational molecular docking assessment of hormone receptor adjuvant drugs: Breast cancer as an example. , 2009, Pathophysiology : the official journal of the International Society for Pathophysiology.