WHOI Biology Department
| Research Interests | Members of the Lab | Recent Publications | Reprints/Information |
|---|
Spring 2004 Course: 7.432 Topics
in Physiology and Biochemistry: Marine Mammal Toxicology
Spring 2003 Course: 7.437 Topics
in Molecular Biological Oceanography: Genomic Approaches
in Marine Science
Here are some of the main research projects underway in the laboratory:
Phylogenetic diversity and molecular evolution of the AHR and the
PAS gene family.
To explore the diversity and comparative biochemistry of AHRs, we
have obtained full or partial sequences of more than 30 AHRs from two dozen
aquatic species, including birds, marine mammals, fishes, an amphibian,
a tunicate, and mollusks. We have compared the structures and functions
of these and other AHRs. These studies have revealed a greater diversity
of AHR genes in fishes as compared to mammals. Initially this involved
the identification of the second AHR form (AHR2) in fishes, while more
recently we have found evidence of additional AHR gene diversity in bony
and cartilaginous fishes. For example, in some species of bony fishes,
duplications at the AHR1 and AHR2 loci have produced up to five distinct
AHR genes in a single fish species (the pufferfish Takifugu rubripes).
These studies also have shown that invertebrate AHRs are unable to bind
the typical ligands of vertebrate AHRs, such as TCDD and BNF. These
studies have been summarized in a recent review and related papers:
Hahn, M. E., Karchner, S. I., Evans, B. R., Franks, D. G., Merson, R. R.,
and Lapseritis, J. M. (2006). Unexpected diversity of aryl hydrocarbon receptors
in non-mammalian vertebrates: Insights from comparative genomics. Journal
of Experimental Zoology (in press).
Hahn, M.E. (2002) Aryl hydrocarbon receptors: Diversity and Evolution. Chem.-Biol. Interact. 141: 131-160.
Hahn, M. E., Merson, R. R., and Karchner, S. I. (2005). Xenobiotic Receptors
in Fishes: Structural and Functional Diversity and Evolutionary
Insights. In Biochemistry and Molecular Biology of Fishes. Vol. 6
- Environmental Toxicology (T. W. Moon, and T. P. Mommsen, Eds.), pp. 191-228.
Hahn, M.E. (1998) The Aryl Hydrocarbon Receptor: A Comparative Perspective. Comp. Biochem. Physiol. 121C(3):23-53.
Hahn, M.E., Karchner, S.I., Shapiro, M.A., and Perera, S.A. (1997) Molecular evolution of two vertebrate aryl hydrocarbon (dioxin) receptors (AHR1 and AHR2) and the PAS family. Proc. Natl. Acad. Sci. U.S.A. 94: 13743-13748 .
AHR Signaling in Mammalian and Nonmammalian Models.
The overall objective of this project is to utilize several vertebrate
model systems (fish, mouse cells, human cells) to investigate the function
of the AHR signaling pathway and its role in normal developmental processes
and in the developmental toxicity of chlorinated dioxins and related chemicals.
The studies take advantage of the fact that fish possess AHR and AHRR paralogs
that are co-orthologs of the mammalian AHR and AHRR genes. Some
recent papers include:
Evans, B. R., Karchner, S. I., Franks, D. G., and Hahn, M. E. (2005). Duplicate aryl hydrocarbon receptor repressor genes (ahrr1 and ahrr2) in the zebrafish Danio rerio: Structure, function, evolution, and AHR-dependent regulation in vivo. Arch. Biochem. Biophys. 441, 151-167.
Karchner, S. I., Franks, D. G., and Hahn, M. E. (2005). AHR1B, a new functional
aryl hydrocarbon receptor in zebrafish: tandem arrangement of ahr1b
and ahr2 genes. Biochem. J., 392: 153-161.
Karchner, S. I., and Hahn, M. E. (2004). Pufferfish (Fugu rubripes)
aryl hydrocarbon receptors: unusually high diversity in a compact genome.
Mar. Environ. Res. 58, 139-140 (abstract).
Yang, X., Liu, D., Murray, T. J., Mitchell, G. C., Hestermann, E. V., Karchner,
S. I., Merson, R. R., Hahn, M. E., and Sherr, D. H. (2005). The Aryl Hydrocarbon
Receptor Constitutively Represses c-myc Transcription in Human Mammary Tumor
Cells. Oncogene 24: 7869–7881.
Karchner, S.I., Franks, D.G., Powell, W.H., and Hahn, M.E. (2002) Regulatory
Interactions Among Three Members of the Vertebrate Aryl Hydrocarbon
Receptor Family: AHR Repressor, AHR1, and AHR2. J. Biol. Chem.
277: 6949-6959.
Karchner, S.I., Powell, W.H., and Hahn, M.E. (1999) Structural and
Functional Characterization of Two Highly Divergent Aryl Hydrocarbon
Receptors in the teleost Fundulus heteroclitus. Evidence for a
novel class of ligand-binding bHLH-PAS factors. Journal of
Biological Chemistry 274: 33814-33824 .
Mechanisms and Consequences of Evolved PCB/Dioxin Resistance in Killifish.
Another research project in our lab involves studies on the evolution
of PCB/dioxin resistance following long-term exposure of fish to dioxins
and PCBs at Superfund sites. As part of the Superfund
Basic Research Program at Boston University, we are investigating
the role of AHRs in the mechanism of this evolved resistance. This
work is described on the Superfund
Basic Research Program web site. We are grateful to the National Institute of Environmental Health
Sciences and the Environmental Protection
Agency for supporting this work. Some recent papers include:
Merson, R. R., Franks, D. G., Karchner, S. I., and Hahn, M. E. (2006).
Development and characterization of polyclonal antibodies against the aryl
hydrocarbon receptor protein family (AHR1, AHR2, and AHR repressor) of Atlantic
killifish Fundulus heteroclitus. Comp Biochem Physiol C Toxicol
Pharmacol 142, 85-94.
Hahn, M.E., Karchner, S.I., Franks, D.G., and Merson, R.R. (2004) Aryl hydrocarbon receptor polymorphisms and dioxin resistance in Atlantic killifish (Fundulus heteroclitus). Pharmacogenetics 14:131-146.
W.H. Powell, H.G. Morrison, E.J. Weil, S.I. Karchner, M.L. Sogin, J.J.
Stegeman, and M.E. Hahn. (2004) Cloning and analysis of the CYP1A
promoter from the Atlantic killifish (Fundulus heteroclitus). Marine
Environmental Research 58: 119-124.
Meyer, J.N., Wassenberg, D.M., Karchner, S.I., Hahn, M.E., and DiGiulio,
R.T. (2003) Expression and inducibility of aryl hydrocarbon receptor
(AHR) pathway genes in wild-caught killifish (Fundulus heteroclitus)
with different contaminant exposure histories. Environ.
Toxicol. Chem. 22: 2337-2343.
Bello, S.M., Franks, D.G., Stegeman, J.J., and Hahn, M.E. (2001) Acquired Resistance to Aryl Hydrocarbon Receptor Agonists in a Population of Fundulus heteroclitus from a Marine Superfund site: In Vivo and In Vitro Studies on the Induction of Xenobiotic Metabolizing Enzymes. Toxicol. Sci. 60: 77-91.
Mechanism of PCB- and Dioxin-Resistance in Fish in the Hudson
River Estuary: Role of Receptor Polymorphisms
This research, supported by the Hudson River Foundation, is investigating
the role of the AHR signaling pathway in evolved PCB/dioxin resistance
in killifish. We are characterizing polymorphic alleles at the AHR1,
AHR2, and AHR Repressor (AHRR) loci in Hudson River estuary and nearby
populations of the Atlantic killifish Fundulus heteroclitus that
have been shown previously to be sensitive or resistant to PCBs or other
HAHs. All three loci are highly polymorphic (AHR1: 45 SNPs; AHR2:
30 SNPs; AHRR: 38 SNPs). The distribution of SNPs and non-synonymous
SNPs and inferred haplotypes (specific arrangements of SNPs on a single
chromosome) varies among sites. A substantial fraction of the inferred
haplotypes for each gene are site specific. Some AHR1 and AHR2 haplotypes
are more frequently observed in fish from contaminated sites, whereas other
haplotypes were under-represented in these fish. In contrast, AHRR
haplotypes were evenly distributed among the five sites in the HR estuary.
These results provide the first large-scale characterization of AHR gene
family variability among sites and identifies specific AHR1 and AHR2 haplotypes
as candidates for functional characterization in relation to the mechanism
of evolved PCB/dioxin resistance in killifish.
The AHR as a Chemical Susceptibility Gene.
In a series of studies, we are characterizing the AHR in marine mammals,
birds, and fish in relation to its possible role in mediating species differences
in sensitivity to HAH toxicity. Some of these projects are funded
by the WHOI Sea Grant Program.
For example,
• AHR in beluga
whales and other marine mammals
• Impact of Environmental
Contaminants on Aquatic Birds: The Molecular Basis of Differential Dioxin
Sensitivity
• Novel Biomarkers
of Dioxin Effects
Jensen, B. A., and Hahn, M. E. (2001). cDNA cloning and characterization
of a high affinity aryl hydrocarbon receptor in a cetacean, the beluga, Delphinapterus
leucas. Toxicol. Sci. 64, 41-56.
Kim, E.-Y., and Hahn, M. E. (2002). cDNA cloning and characterization of
an aryl hydrocarbon receptor from the harbor seal (Phoca vitulina):
A biomarker of dioxin susceptibility? Aquat. Toxicol. 58, 57-73.
Karchner, S. I., Kennedy, S. W., Trudeau, S., and Hahn, M. E. (2000). Towards
a molecular understanding of species differences in dioxin sensitivity:
Initial characterization of Ah receptor cDNAs in birds and an amphibian.
Mar. Environ. Res. 50, 51-56.
Karchner, S. I., Franks, D. G., Kennedy, S. W., and Hahn, M. E. (2006).
The molecular basis for differential dioxin sensitivity in birds: Role
of the aryl hydrocarbon receptor. Proc. Natl.
Acad. Sci. U.S.A. 103, 6252-6257.
Natural Ligands for the AHR
The AHR was originally discovered because of its role in mediating
effects of synthetic HAHs. However, receptors and enzymes that appear to
function primarily in adaptive responses to xenobiotic chemicals often
have endogenous regulators and substrates as well. Similarly, receptors
for well-known hormones and growth factors often are targets of natural
products. We are involved in a series of collaborative studies to understand
the chemical specificity of vertebrate and invertebrate AHRs. These
studies have identified a number of marine natural products, including
some persistent brominated and chlorinated aromatics, that can activate
the AHR. In addition, natural indoles isolated from mammalian tissues
can act as AHR agonists and natural flavonoids can act as antagonists.
Vetter, W., Hahn, M. E., Tomy, G., Ruppe, S., Vatter, S., Chahbane,
N., Lenoir, D., Schramm, K.-W., and Scherer, G. (2005). Biological activity
and physico-chemical parameters of the marine halogenated natural products
2,3,3´,4,4´,5,5´-heptachloro-2´-methyl-1,2´-bipyrrole
(Q1) and 2,4,6-tribromoanisole (TBA). Arch. Environ. Contam. Toxicol.
48, 1-9.
Tittlemier, S.A., Kennedy, S.W., Hahn, M.E., Reddy, C.M., and Norstrom,
R.J. (2003) Naturally-produced halogenated dimethyl bipyrroles bind
to the Ah receptor and induce cytochrome P4501A and porphyrin accumulation
in chicken embryo hepatocytes. Environ.
Toxicol. Chem. 22: 1497-1506.
Song, J., Clagett-Dame, M., Peterson, R.E., Hahn, M.E., Westler, W.M., Sicinski, R.R., and DeLuca, H.F. (2002) A Novel Ligand for the Aryl Hydrocarbon Receptor Isolated from Lung. Proc. Natl. Acad. Sci. U.S.A. 99: 14694-14699.
Billiard, S.M., Hahn, M.E., Franks, D.G., Peterson, R.E., Bols, N.C., and Hodson, P.V. (2002) Binding of polycyclic aromatic hydrocarbons (PAHs) to teleost aryl hydrocarbon receptors (AHRs). Comparative Biochemistry and Physiology B 133: 55-68.
Mechanisms of Response to Oxidative Stress
During embryonic and fetal development, animals are especially sensitive
to chemicals causing oxidative stress. The developmental expression and
inducibility of anti-oxidant defenses is a critical factor affecting susceptibility
to oxidants at these early life stages. In mammalian systems, oxidant
and pro-oxidant chemicals elicit an anti-oxidant response, referred to as
the “oxidative stress response (OSR)”, which involves the increased expression
of genes whose products act to mitigate the oxidant challenge. We have initiated
studies to establish zebrafish as a model for studying mechanisms of developmental
toxicity and the role of oxidative stress.
Karchner, S. I., Franks, D. G., Kennedy, S. W., and Hahn, M. E. (2006). The molecular basis for differential dioxin sensitivity in birds: Role of the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. U.S.A. 103, 6252-6257.
Merson, R. R., Franks, D. G., Karchner, S. I., and Hahn, M. E. (2006).
Development and characterization of polyclonal antibodies against the aryl
hydrocarbon receptor protein family (AHR1, AHR2, and AHR repressor) of Atlantic
killifish Fundulus heteroclitus. Comp Biochem Physiol C Toxicol
Pharmacol 142, 85-94.
Evans, B. R., Karchner, S. I., Franks, D. G., and Hahn, M. E. (2005). Duplicate aryl hydrocarbon receptor repressor genes (ahrr1 and ahrr2) in the zebrafish Danio rerio: Structure, function, evolution, and AHR-dependent regulation in vivo. Arch. Biochem. Biophys. 441, 151-167.
Karchner, S. I., Franks, D. G., and Hahn, M. E. (2005). AHR1B, a new functional
aryl hydrocarbon receptor in zebrafish: tandem arrangement of ahr1b
and ahr2 genes. Biochem. J., 392: 153-161.
Vetter, W., Hahn, M. E., Tomy, G., Ruppe, S., Vatter, S., Chahbane, N.,
Lenoir, D., Schramm, K.-W., and Scherer, G. (2005). Biological activity
and physico-chemical parameters of the marine halogenated natural products
2,3,3´,4,4´,5,5´-heptachloro-2´-methyl-1,2´-bipyrrole
(Q1) and 2,4,6-tribromoanisole (TBA). Arch. Environ. Contam. Toxicol.
48, 1-9.
Hahn, M. E., Merson, R. R., and Karchner, S. I. (2005). Xenobiotic Receptors
in Fishes: Structural and Functional Diversity and Evolutionary
Insights. In Biochemistry and Molecular Biology of Fishes. Vol. 6
- Environmental Toxicology (T. W. Moon, and T. P. Mommsen, Eds.), pp. 191-228.
in
press.
Hahn, M.E., Karchner, S.I., Franks, D.G., and Merson, R.R. (2004) Aryl hydrocarbon receptor polymorphisms and dioxin resistance in Atlantic killifish (Fundulus heteroclitus). Pharmacogenetics 14:131-146.
Hahn, M.E., Jensen, B.A., Kim, E.-Y., Karchner, S.I., Franks, D.G., Lapseritis, J.M., Whalen, K.E., and Carvan, M.J. (2003) Molecular and cellular approaches to understanding the sensitivity of marine mammals to persistent organic pollutants. Organohalogen Compounds 62: 253-256.
Hahn, M.E., Karchner, S.I., and Franks, D.G. (2003) The Ah receptor and
its ligands: A comparative perspective. Organohalogen Compounds
65: 110-113.
Hahn, M.E. (2003) Chapter 14: Evolutionary and Physiological Perspectives on Ah Receptor Function and Dioxin Toxicity, in Dioxins and Health, Second Edition, Schecter, A. and Gasiewicz, T.A., Editor., John Wiley & Sons: p. 559-602.
Hart, C.A., Nisbet, I.C.T., Kennedy, S.W., and Hahn, M.E. (2003) Gonadal feminization and halogenated environmental contaminants in common terns (Sterna hirundo): Evidence that ovotestes in male embryos do not persist to the prefledgling stage. Ecotoxicology 12: 125-140.
Meyer, J.N., Wassenberg, D.M., Karchner, S.I., Hahn, M.E., and DiGiulio,
R.T. (2003) Expression and inducibility of aryl hydrocarbon receptor
(AHR) pathway genes in wild-caught killifish (Fundulus heteroclitus)
with different contaminant exposure histories. Environ.
Toxicol. Chem. 22: 2337-2343.
Tittlemier, S.A., Kennedy, S.W., Hahn, M.E., Reddy, C.M., and Norstrom,
R.J. (2003) Naturally-produced halogenated dimethyl bipyrroles bind
to the Ah receptor and induce cytochrome P4501A and porphyrin accumulation
in chicken embryo hepatocytes. Environ.
Toxicol. Chem. 22: 1497-1506.
Song, J., Clagett-Dame, M., Peterson, R.E., Hahn, M.E., Westler, W.M., Sicinski, R.R., and DeLuca, H.F. (2002) A Novel Ligand for the Aryl Hydrocarbon Receptor Isolated from Lung. Proc. Natl. Acad. Sci. U.S.A. 99: 14694-14699.
Andreasen, E.A., Hahn, M.E., Heideman, W., Peterson, R.E., and Tanguay, R.L. (2002) The zebrafish (Danio rerio) aryl hydrocarbon receptor type 1 (zfAHR1) is a novel vertebrate receptor. Mol. Pharmacol. 62: 234-249.
Billiard, S.M., Hahn, M.E., Franks, D.G., Peterson, R.E., Bols, N.C., and Hodson, P.V. (2002) Binding of polycyclic aromatic hydrocarbons (PAHs) to teleost aryl hydrocarbon receptors (AHRs). Comparative Biochemistry and Physiology B 133: 55-68.
Hahn, M.E. (2002) Aryl hydrocarbon receptors: Diversity and Evolution. Chem.-Biol. Interact. 141: 131-160.
Kim, E.-Y., Hahn, M.E., Iwata, H., Tanabe, S., and Miyazaki, N. (2002) cDNA cloning of an aryl hydrocarbon receptor from Baikal Seals (Phoca sibirica). Mar. Environ. Res. 54: 285-289.
Karchner, S.I., Franks, D.G., Powell, W.H., and Hahn, M.E. (2002) Regulatory Interactions Among Three Members of the Vertebrate Aryl Hydrocarbon Receptor Family: AHR Repressor, AHR1, and AHR2. J. Biol. Chem. 277: 6949-6959.
Powell, W.H. and Hahn, M.E. (2002) Identification and Functional Characterization of Hypoxia-inducible factor 2a from the marine teleost, Fundulus heteroclitus: Interaction of HIF-2a with two ARNT2 splice variants. J. Exp. Zool.-Molecular and Developmental Evolution 294: 17-29.
Hahn, M.E. (2002) Biomarkers and Bioassays for Detecting Dioxin-like Compounds in the Marine Environment. Science of the Total Environment 289:49-69
Karchner, S.I., Powell, W.H., and Hahn, M.E. (1999) Structural and Functional Characterization of Two Highly Divergent Aryl Hydrocarbon Receptors in the teleost Fundulus heteroclitus. Evidence for a novel class of ligand-binding bHLH-PAS factors. Journal of Biological Chemistry 274: 33814-33824 .
Abnet, C.C., Tanguay, R.L., Hahn, M.E., Heideman, W., and Peterson, R.E. (1999) Two forms of aryl hydrocarbon receptor type 2 in rainbow trout (Oncorhynchus mykiss): Evidence for differential expression and enhancer specificity.Journal of Biological Chemistry 274: 15159-15166.
Hahn, M.E. (1998) Mechanisms of innate and acquired resistance to dioxin-like compounds. Reviews in Toxicology. Series B - Environmental Toxicology 2: 395-443. (Abstract)
Hahn, M.E. (1998) The Aryl Hydrocarbon Receptor: A Comparative Perspective. Comp. Biochem. Physiol. 121C(3):23-53.
Hahn, M.E., Karchner, S.I., Shapiro, M.A., and Perera, S.A. (1997) Molecular evolution of two vertebrate aryl hydrocarbon (dioxin) receptors (AHR1 and AHR2) and the PAS family. Proc. Natl. Acad. Sci. U.S.A. 94: 13743-13748 .
email:
Return to Biology Department Home Page
(Last updated July 5, 2006)