Timing is everything: Consequences of transient and sustained AhR activity

doi:10.1016/j.bcp.2008.10.028

Biochemical Pharmacology

Volume 77, Issue 6, 15 March 2009, Pages 947-956

https://doi.org/10.1016/j.bcp.2008.10.028 Get rights and content

Abstract

The aryl hydrocarbon receptor (AhR) was implicated as a mediator of xenobiotic toxicity over three decades ago. Although a complete picture continues to elude us, investigations by many laboratories during the ensuing period have revealed much about AhR biology in normal physiological processes, as well as the toxicities induced by the dioxins and related polychlorinated aromatic hydrocarbons. The findings are captured in numerous excellent reviews. This commentary attempts to inject a new perspective on some new as well as frequently overlooked observations in the context of established receptor properties. Specifically, we examine the impact of transient versus sustained receptor activation on AhR biology, and explore the potential role for cytochrome P450 expression in regulating AhR activity amongst various tissues. The growing recognition that AhR action functions through multiple mechanisms serves to further highlight the importance of limiting prolonged receptor activation.

Section snippets

Mechanisms regulating sustained AhR activity

The eukaryotic Per-ARNT-Sim (PAS) domain protein family contains several members that function as sensors of extracellular signals and environmental stresses affecting growth and development [1]. Among these members, the aryl hydrocarbon receptor (AhR) regulates adaptive and toxic responses to a variety of chemical pollutants, including polycyclic aromatic hydrocarbons and polychlorinated dioxins, most notably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The AhR is a soluble cytosolic

The role of other AhR-responsive P450s

The cytochrome P450 subfamilies CYP1 to CYP4 are responsible for most of the metabolism of foreign compounds, possess unique yet overlapping substrate specificities, and are often regulated by substrate-induced activation of gene transcription. Amongst these, several P450s are AhR target genes, including CYP1A1, 1A2, and 1B1, as well as CYP2S1 [57] and murine Cyp2a5 [58], [59]. Conventional wisdom maintains that the AhR is a biosensor for compounds metabolized by these isozymes, and the

Multiple mechanisms of AhR action

The preceding discussion sought to illustrate that AhR signaling is tightly regulated, and that prolonged or persistent receptor activity can lead to deleterious consequences. A growing body of evidence is beginning to reveal a deeper level of complexity in AhR biology depicted by numerous, varied mechanisms. These are illustrated in Fig. 2. Upon DNA binding, the AhR/ARNT heterodimer forms the scaffold for multiple coactivator complexes associated with the receptor (Fig. 2, Scheme 1). Each

Conclusion

Identification of new AhR roles and recent advances in previously identified mechanisms firmly establish the AhR as an important regulator of normal developmental and homeostatic processes. Our growing awareness of the complexity behind AhR biology is underscored by our inability to mechanistically resolve TCDD toxicity despite decades of research. Therefore, it stands to reason that the basis for TCDD toxicity may only be revealed once we understand the role played by the receptor in normal

Acknowledgments

The authors wish to thank John Holmes for the artwork. This work was supported by grants from the National Institute of Environmental Health Sciences: R01ES007800, R01ES012018 and F32ES013588.

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A dozen bHLH-PAS transcription factors have evolved since the dawn of the animal kingdom; nine of them have mutual orthologs between arthropods and vertebrates. These proteins are master regulators in a range of developmental processes from organogenesis, nervous system formation and functioning, to cell fate decisions defining identity of limbs or photoreceptors for color vision. Among the functionally best conserved are bHLH-PAS proteins acting in the animal circadian clock. On the other side of the spectrum are fundamental physiological mechanisms such as those underlying xenobiotic detoxification, oxygen homeostasis, and metabolic adaptation to hypoxia, infection or tumor progression. Predictably, malfunctioning of bHLH-PAS regulators leads to pathologies. Performance of the individual bHLH-PAS proteins is modulated at multiple levels including dimerization and other protein–protein interactions, proteasomal degradation, and by binding low-molecular weight ligands. Despite the vast evolutionary gap dividing arthropods and vertebrates, and the differences in their anatomy, many functions of orthologous bHLH-PAS proteins are remarkably similar, including at the molecular level. Our phylogenetic analysis shows that one bHLH-PAS protein type has been lost during vertebrate evolution. This protein has a unique function as a receptor of the sesquiterpenoid juvenile hormones of insects and crustaceans. Although some other bHLH-PAS proteins are regulated by binding small molecules, the juvenile hormone receptor presents an unprecedented case, since all other non-peptide animal hormones activate members of the nuclear receptor family. The purpose of this review is to compare and highlight parallels and differences in functioning of bHLH-PAS proteins between insects and vertebrates.
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The representative mechanism of toxicity for some PTSs, including polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs), is dioxin-like activity (Hilscherova et al., 2000; Lee et al., 2017a, 2020; Takigami et al., 2005; Xia et al., 2014; Zhang et al., 2017). Dioxin-like chemicals (DLCs) induce a variety of toxic effects such as lethality, carcinogenesis, and tumor promotion by activating AhR (Giesy et al., 2002; Mitchell and Elferink, 2009). AhR is mainly activated by endogenous physiological ligands and is also activated by the environmental ligands of contaminants (Quintana, 2013).
In the present study, we investigated the contamination status of dioxin-like chemicals (DLCs) and potential toxic effects associated with river and coastal sediments from two large estuaries of South Korea. Sediments collected from the Yeongsan River and the Nakdong River estuaries were analyzed for several DLCs, including polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), coplanar polychlorinated biphenyls (co-PCBs), and polycyclic aromatic hydrocarbons (PAHs). Greater concentrations of target DLCs (except for PCDDs in Nakdong River) were found in the inland creeks with decreasing trends towards estuarine and coastal areas in both regions. The result indicated that the elevated DLCs were attributable to the surrounding land use activities, such as point sources of industrial and municipal areas from the inland regions. Principal component analysis and positive matrix factorization model revealed that major sources of PCDD/Fs and PAHs in sediments were fly ash and dust, and petroleum and diesel emission, respectively. The dioxin-like activities of the sediments ranged from 0.98 to 88% of the maximal induction elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin, which generally explained the sedimentary contamination by the target DLCs. Dioxin-like activity in sediments from the artificial lake and inland creek of the Nakdong River Estuary was mostly explained by the targeted DLCs (~75%). However, the contribution of known DLCs from the sediments of the Yeongsan River Estuary was relatively low (~35%) compared to that of the Nakdong River Estuary, suggesting the presence of unknown DLCs in sediments. Overall, the distribution of DLCs quite varied by region, generally reflecting the difference in the surrounding land use activity. In the future, it is needed to study the distribution, sources, and potential ecological effects of unknown toxic substances in coastal sediments.
High throughput data-based, toxicity pathway-oriented development of a quantitative adverse outcome pathway network linking AHR activation to lung damages
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The quantitative adverse outcome pathway (qAOP) is proposed to inform dose-responses at multiple biological levels for the purpose of toxicity prediction. So far, qAOP models concerning human health are scarce. Previously, we proposed 5 key molecular pathways that led aryl hydrogen receptor (AHR) activation to lung damages. The present study assembled an AOP network based on the gene expression signatures of these toxicity pathways, and validated the network using publicly available high throughput data combined with machine learning models. In addition, the AOP network was quantitatively evaluated with omics approaches and bioassays, using 16HBE-CYP1A1 cells exposed to benzo(a)pyrene (BaP), a prototypical AHR activator. Benchmark dose (BMD) analysis of transcriptomics revealed that AHR gene held the lowest BMD value, whereas AHR pathway held the lowest point of departure (PoD) compared to the other 4 pathways. Targeted bioassays were further performed to quantitatively understand the cellular responses, including ROS generation, DNA damage, interleukin-6 production, and extracellular matrix increase marked by collagen expression. Eventually, response-response relationships were plotted using nonlinear model fitting. The present study developed a highly reliable AOP model concerning human health, and validated as well as quantitatively evaluated it, and such a method is likely to be adoptable for risk assessment.
Effect-directed identification of novel aryl hydrocarbon receptor-active aromatic compounds in coastal sediments collected from a highly industrialized area
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In previous studies, several aryl hydrocarbon receptor (AhR) agonists, including benzo[j]fluoranthene (BjF), benz[b]anthracene (BbA), and enoxolone, were successfully identified in organic extracts of sediments from highly industrialized areas in South Korea using EDA (Cha et al., 2019; Kim et al., 2019; Lee et al., 2020). AhR that responds to external chemicals, such as polycyclic aromatic hydrocarbons (PAHs), mediates toxic reactions, including mutagenicity, carcinogenicity, and developmental toxicity (Mitchell and Elferink, 2009). AhR-active compounds are used or generated as byproducts in industries, with rivers surrounding industrial complexes introducing them to coastal areas where they could accumulate in sediments (Kim et al., 2019).
In this study, we identified major aryl hydrocarbon receptor (AhR) agonists in the sediments from Yeongil Bay (n = 6) using effect-directed analysis. Using the H4IIE-luc bioassays, great AhR-mediated potencies were found in aromatic fractions (F2) of sediment organic extracts from silica gel column chromatography and sub-fractions (F2.6–F2.8) from reverse phase-HPLC. Full-scan mass spectrometric analysis using GC-QTOFMS was conducted to identify novel AhR agonists in highly potent fractions, such as F2.6–F2.8 of S1 (Gumu Creek). Selection criteria for AhR-active compounds consisted of three steps, including matching factor of NIST library (≥70), aromatic structures, and the number of aromatic rings (≥4). Fifty-nine compounds were selected as tentative AhR agonist candidates, with the AhR-mediated activity being assessed for six compounds for which standard materials were available commercially. Of these compounds, 20-methylcholanthrene, 7-methylbenz[a]anthracene, 10-methylbenz[a]pyrene, and 7,12-dimethylbenz[a]anthracene exhibited significant AhR-mediated potency. Relative potency values of these compounds were determined relative to benzo[a]pyrene to be 3.2, 1.4, 1.2, and 0.2, respectively. EPA positive matrix factorization modeling indicated that the sedimentary AhR-active aromatic compounds primarily originated from coal combustion and vehicle emissions. Potency balance analysis indicated that four novel AhR agonists explained 0.007% to 1.7% of bioassay-derived AhR-mediated potencies in samples.
Characterization of marine-derived halogenated indoles as ligands of the aryl hydrocarbon receptor
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The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor thought to mediate a number of physiological roles in the body, is becoming a target of interest for the development of new therapeutics. However, previous research has demonstrated that the downstream effects of AhR ligands cannot be predicted based simply on whether a ligand acts as an agonist or antagonist and the persistence of AhR signaling is thought to be a key determining feature. The current study investigated the AhR activity of four halogenated indoles isolated from the New Zealand red alga, Rhodophyllis membranacea: 4,7-dibromo-2,3-dichloroindole (4DBDCI), 7-bromo-2,3-dichloro-6-iodoindole (BDCII), 6,7-dibromo-2,3-dichloroindole (6DBDCI) and 2,6,7-tribromo-3-chloroindole (TBCI). Their ability to activate AhR signaling, measured as CYP1A1 activity via the ethoxyresorufin O-deethylase (EROD) assay, was determined in human HepG2, mouse Hepa1c1c7 and rat H4IIE liver cancer cells. All four compounds induced CYP1A1 activity in HepG2 cells, suggesting they all acted as AhR agonizts. 4DBDCI was particularly efficacious, inducing an 11-fold increase. Hepa1c1c7 and H4IIE cells, however, were generally less responsive to the halogenated indoles. All four compounds were persistent AhR agonizts, inducing peak CYP1A1 activity after 72 h. Moreover, the 2,3,6,7-substituted BDCII, 6DBDCI and TBCI, but not 4DBDCI, competed with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for AhR binding as observed by the inhibition of TCDD-induced CYP1A1 activity. Overall, the current study has characterized four previously untested AhR ligands, highlighting differences in species sensitivity and persistence of signaling to provide a framework for their potential future use.
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Transient AhR activation by (endogenous) ligands is important in the maintenance of cell homeostasis (Bock, 2013; Mitchell et al., 2006). In contrast, persistent (or sustained) AhR induction may culminate in adverse toxic outcomes (e.g. developmental toxicity), such as those observed following TCDD exposure (Mitchell et al., 2006; Mitchell and Elferink, 2009). Altogether, this absence of sustained AhR induction by the fume condensate extracts of bitumen and oxidized asphalt tested compliments the current finding that both test materials tested negative for in vitro and in vivo developmental toxicity.
The potential developmental toxicity and mode-of-action of fume condensate extracts of bitumen and oxidized asphalt were evaluated in the aryl hydrocarbon receptor (AhR) CALUX assay, the zebrafish embryotoxicity test (ZET), and the mouse embryonic stem cell test (mEST). In the AhR CALUX assay, both fume condensate extracts showed a concentration-dependent AhR induction following 6-h of exposure, but this activity was substantially reduced after 24-h, indicating a transient AhR activation. The main effect observed in the ZET was early embryonic lethality that occurred mostly in the 24 h-post-fertilization (hpf). This typically reflects non-specific toxicity rather than in vitro developmental toxicity of the fume condensate extracts tested since this effect was not seen as a result of the whole cumulative exposure period in the ZET (up to 96 hpf). No malformations were seen in any zebrafish embryo exposed to these fume condensate extracts, although some developed pericardial and/or yolk-sac edemas. Furthermore, both fume condensate extracts tested negative in the mEST. In conclusion, the results show that fume condensate extracts of bitumen and oxidized asphalt do not induce any in vitro developmental toxicity, which is in line with the results observed in the in vivo prenatal developmental toxicity studies performed with the same materials.

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¹: Current address: Department of Biological Sciences, Boise State University, Boise, ID 83725-1515, United States.

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CommentaryTiming is everything: Consequences of transient and sustained AhR activity

Abstract

Section snippets

Mechanisms regulating sustained AhR activity

The role of other AhR-responsive P450s

Multiple mechanisms of AhR action

Conclusion

Acknowledgments

The Journal of Biological Chemistry

The Journal of Biological Chemistry

The Journal of Biological Chemistry

The Journal of Biological Chemistry

The Journal of Biological Chemistry

The Journal of Biological Chemistry

Biochemical Pharmacology

The Journal of Biological Chemistry

Archives of Biochemistry and Biophysics

The Journal of Biological Chemistry

The Journal of Biological Chemistry

Chemico-Biological Interactions

The Journal of Biological Chemistry

Toxicology and Applied Pharmacology

Mutation Research

Neuroscience Letters

Immunopharmacology

Lancet

Archives of Biochemistry and Biophysics

Archives of Biochemistry and Biophysics

Journal of Biological Chemistry

Journal of Biological Chemistry

The Journal of Biological Chemistry

The Journal of Biological Chemistry

Biochemistry and Biophysics Research Communication

Journal of Biological Chemistry

The PAS superfamily: sensors of environmental and developmental signals

Annual Review of Pharmacology and Toxicology

Hepatitis B virus X-associated protein 2 is a subunit of the unliganded aryl hydrocarbon receptor core complex and exhibits transcriptional enhancer activity

Molecular and Cellular Biology

Multiple roles of ligand in transforming the dioxin receptor to an active basic helix-loop-helix/PAS transcription factor complex with the nuclear protein ARNT

Molecular and Cellular Biology

Drug-metabolizing enzymes, polymorphisms and interindividual response to environmental toxicants

Clinical Chemistry and Laboratory Medicine

Control of cytochrome P1-450 gene expression by dioxin.

Science (New York, NY)

Induction of cytochrome P4501A1

Annual Review of Pharmacology and Toxicology

Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development

Proceedings of the National Academy of Sciences of the United States of America

Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor

Genes Cells

Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor.

Science (New York, NY)

Lesions of aryl-hydrocarbon receptor-deficient mice

Veterinary Pathology

The aryl hydrocarbon receptor: studies using the AHR-null mice

Drug Metabolism and Disposition: The Biological Fate of Chemicals

Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice

Proceedings of the National Academy of Sciences of the United States of America

Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types

Proceedings of the National Academy of Sciences of the United States of America

Developmental expression of two members of a new class of transcription factors. I. Expression of aryl hydrocarbon receptor in the C57BL/6N mouse embryo

Developmental Dynamics

Commentary
Timing is everything: Consequences of transient and sustained AhR activity