ProjectDevelopmental Effects of Superfund Hydrocarbon Mixtures in Fundulus heteroclitus
Project Leaders: Richard T. Di Giulio, David E. Hinton, Marjorie Oleksiak
Publications ↓Project Description
Previous work in this project demonstrated that extracts of sediments from an estuary adjacent to a PAH dominated Superfund site in VA are highly teratogenic to embryos of the killifish, Fundulus heteroclitus, with cardiovascular defects the most pronounced effect observed. Studies with model PAHs demonstrated marked synergistic interactions between PAH-type AHR agonists and CYP1A inhibitors. Current risk assessment approaches for PAHs, however, assume an additive model of toxicity for PAHs. Hypoxia is an important variable affecting development as well as comprising a natural stressor in estuaries. Thus, the overarching goal of this project is to elucidate interactive effects on development and mechanisms underling such effects by PAH mixtures and hypoxia in Fundulus. The Specific Aims are:
- To characterize the effects of a Superfund site PAH mixture on development in Fundulus with imaging, biochemical and molecular tools.
- To elucidate interactive effects and underlying mechanisms of representative CYP1A inducers (AHR agonists) and inhibitors on development.
- To elucidate interactive effects and underlying mechanisms of model PAHs and hypoxia on development in Fundulus.
- To determine effects of selected PAH mixtures on development in other models employed in the Center.
- To develop practical biomarkers for developmental effects of hydrocarbon mixtures in vertebrates.
This study will integrate three complimentary experimental methodologies:
- imaging and pathology,
- analysis of gene expression, particularly by microarray, and
- biochemical analyses, particularly of responses mediated by the aryl hydrocarbon receptor pathway, the hypoxia inducible factor pathway, and oxidative stress.
This project will elucidate toxic interactions of a class of chemicals (PAHs) that is exhibiting steady increase in the environment, invariably occurs in mixtures, and for which current assessments may underestimate risks for developmental effects. The model for this project, Fundulus, has great ecological relevance, is an excellent sentinel species for coastal ecosystems, and provides a useful model for developmental studies relevant to human health.
Description ↑Publications
Wills, L.P., D. Jung, K. Koerhn, S. Zhu, K.L. Willett, D.E. Hinton, and R.T. Di Giulio. 2010. Comparative chronic liver toxicity of benzo[a]pyrene in two populations of the Atlantic killifish (Fundulus heteroclitus) with different exposure histories. Environl Health Perspect.
Oleksiak, M. F. 2010. Genomic approaches with natural fish populations. Journal of Fish Biology Vol. 76, No. 8., pp. 1903-1925.
Bozinovic, G, and M.F. Oleksiak. 2010. Embryonic gene expression among pollutant resistant and sensitive Fundulus heteroclitus populations. Aquatic Toxicology. PMC Journal - In Process.
Fleming, C.R., S.M. Billiard, and R.T. Di Giulio. 2009. Hypoxia inhibits induction of aryl hydrocarbon receptor activity in topminnow hepatocarcinoma cells in an ARNT-dependent manner. Comparative Biochemistry and Physiology (Part C)150:383-389. PMID: 19539049
Jung, D., Y. Cho, Y., L. B. Collins, J.A. Swenberg, and R.T. Di Giulio. 2009. Effects of benzo[a]pyrene on mitochondrial and nuclear DNA damage in Atlantic killifish (Fundulus heteroclitus) from a creosote-contaminated and reference site. Aquat Toxicol 95:44-51. PMC2776085
Timme-Laragy, A.R., L.A. Van Tiem, and R.T. Di Giulio. 2009. Antioxidant responses and NRF2 in synergistic developmental toxicity of PAHs in zebrafish. Toxicol Sci 109:217-227. PMC2721659
Oleksiak, M.F. 2008. Changes in gene expression due to chronic exposure to environmental pollutants. Aquatic Toxicology 90:161-171. PMCID 2584160
Matson, C.W., A.R. Timme-Laragy, and R.T. Di Giulio. 2008. Fluoranthene, but not benzo[a]pyrene, interacts with hypoxia resulting in pericardial effusion and lordosis in developing zebrafish. Chemosphere Volume 74, Issue 1, December 2008, Pages 149-154 .
Di Giulio, R.T. and M.C. Newman. Ecotoxicology. 2008. Pp. 1157-1187 in Klaassen, C.D., ed. Casarett and Doull’s Toxicology. The Basic Science of Poisons, 6th edition. McGraw-Hill, New York.
Billiard, S.M., Meyer, J.N., Wassenberg, D.M., Hodson, P.V., and Di Giulio, R.T. 2008. Nonadditive effects of PAHs on early vertebrate development: mechanisms and implications for risk assessment. Toxicological Sciences. (in press).
Bohonowych, J.E.S., B. Zhao, A. Timme-Laragy, D. Jung, R.T. Di Giulio, and M.S. Denison. 2008. Newspapers and newspaper inks contain agonists for the AH receptor. Toxicological Sciences. 102:278-290.
Di Giulio, R.T., and D.E. Hinton, eds. 2008. The Toxicology of Fishes. Taylor and Francis, Boca Raton, FL (in press).
Di Giulio, R.T. and J.N. Meyer. 2008. Reactive oxygen species and oxidative stress. In: Di Giulio, R.T., and D.E. Hinton, eds. The Toxicology of Fishes. Taylor and Francis, Boca Raton, FL (in press).
Hinton, D.E., H. Segner, D.W.T. Au, S.W. Kullman, and R.C. Hardman. 2008. Liver toxicity. . In: Di Giulio, R.T., and D.E. Hinton, eds. The Toxicology of Fishes. Taylor and Francis, Boca Raton, FL (in press).
Rotchell, J.M., D.E. Hinton, M.R. Miller, R.T. Di Giulio, and G.K. Ostrander. 2008. Chemical carcinogenesis in fishes. In: Di Giulio, R.T., and D.E. Hinton, eds. The Toxicology of Fishes. Taylor and Francis, Boca Raton, FL (in press).
Timme-Laragy, A.R., P.D. Noyes, D.R. Buhler, and R.T. Di Giulio. 2008. CYP1B1 knockdown does not alter synergistic developmental toxicity of polycyclic aromatic hydrocarbons in zebrafish (Danio rerio). Marine Environmental Research. 60:85-87.
Matson, C.W., B.W. Clark, M.J. Jenny, C.R. Fleming, M.E. Hahn, and R.T. Di Giulio. 2008. Development of the morpholino gene knockdown technique in Fundulus heteroclitus: a tool for studying molecular mechanisms in an established environmental model. Aquatic Toxicology. 87:289-295.
Oleksiak, M. F. Toxicogenomics, in: Molecular and Biochemical Toxicology, Fourth Edition, John Wiley and Sons, Inc., Hoboken, NJ (in press).
Benson, W.H., and R.T. Di Giulio, eds. 2007. Genomic Approaches for Cross-Species Extrapolations in Toxicology. Taylor and Francis, New York.
Burnett, K.G., L.J. Bain, W.S. Baldwin, G.C. Callard, S. Cohen, R.T. Di Giulio et al. 2007. Fundulus as the premier teleost model in environmental biology: opportunities for new insights using genomics. Comparative Biochemistry and Physiology Part D: Genomics and Proteomics . 2D:257-286.
Timme-Laragy, A.R., C.J. Cockman, C.W. Matson, and R.T. Di Giulio. 2007. Synergistic induction of AHR regulated genes in developmental toxicity from two model PAHs in zebrafish. Aquatic Toxicology. 85:241-250.
Craft, Elena S., Michelle A. Rau, Richard T. Di Giulio, and Jonathan H. Freedman. 2004. Evidence for the role of p53 in metal-induced activation of metallothionein gene expression. In: Metal Ions in Biology and Medicine: Proceedings of the Eighth International Symposium on Metal Ions in Biology and Medicine. John Libbey Eurotext Publishers, Montrouge, France.
Meyer, Armando. 2003. Oxidative stress in two populations of killifish (Fundulus heteroclitus) with differing contaminant exposure histories. Aquatic Toxicology. 65:377-395.
Meyer, Armando, Jim D. Smith, Gary W. Winston, and Richard T. Di Giulio. 2003. Antioxidant defenses in killifish (Fundulus heteroclitus) exposed to contaminated sediments and model prooxidants: short-term and heritable responses. Aquatic Toxicology. 65(4):377-395.
Meyer, Joel N. and Richard T. Di Giulio. 2003. Heritable adaptation and fitness costs in killifish (Fundulus heteroclitus) inhabiting a polluted estuary. Ecological Applications. 13(2):490-503.
Meyer, Joel N., Deena M. Wassenberg, Sibel I. Karchner, Mark E. Hahn, and Richard T. Di Giulio. 2003. Expression and inducibility of aryl hydrocarbon receptor pathway genes in wild-caught killifish (Fundulus heteroclitus) with different contaminant-exposure histories. Environmental Toxicology and Chemistry. 22(10):2337-2343.
Meyer, Joel and Richard T. Di Giulio. 2002. Patterns of heritability of decreased EROD activity and resistance to PCB 126-induced teratogenesis in laboratory-reared offspring of killifish (Fundulus heteroclitus) from a creosote-contaminated site in the Elizabeth River, VA, USA. Marine Environmental Research. 54(3-5):621-626.
Meyer, Joel N., Diane E. Nacci, and Richard T. Di Giulio. 2002. Cytochrome P4501A (CYP1A) in killifish (Fundulus heteroclitus): heritability of altered expression and relationship to survival in contaminated sediments. Toxicological Sciences. 68(1):69-81.
Wassenberg, Deena M., Erin E. Swails, and Richard T. Di Giulio. 2002. Effects of single and combined exposures to benzo(a)pyrene and 3,3, 4,4 5-pentachlorobiphenyl on EROD activity and development in Fundulus heteroclitus. Marine Environmental Research. 54(3-5):279-283.
Mattie, Michael D. and Jonathan H. Freedman. 2001. Protective effects of aspirin and Vitamin E (a-tocopherol) against copper- and cadmium-induced toxicity. Biochemical and Biophysical Research Communications. 285(4):921-925.
Willett, Kristine L., D. Wassenberg, Laila Lienesch, William Reichert, and Richard T. Di Giulio. 2001. In vivo and in vitro inhibition of CYP1A-dependent activity in Fundulus heteroclitus by the polynuclear aromatic hydrocarbon (PAH) fluoranthene. Toxicology and Applied Pharmacology. 177(3):264-271.