Identification of dioxin-responsive elements (DREs) in the 5′ regions of putative dioxin-inducible genes

doi:10.1016/0009-2797(96)03691-5

Chemico-Biological Interactions

Volume 100, Issue 2, 25 March 1996, Pages 97-112

https://doi.org/10.1016/0009-2797(96)03691-5 Get rights and content

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an exogenous ligand for the cytosolic aryl hydrocarbon receptor (AhR), a ligand-inducible transcription factor whose exact physiological role remains elusive. TCDD has been shown to modulate the expression of a large array of genes, albeit often indirectly, by demonstration of protein or mRNA upregulation. Here, by computer analysis of available promoter sequences, we identify dioxin-responsive elements in the promoter regions of many putative AhR regulated and therefore dioxin-inducible genes.

References (104)

M.P. Holsapple et al.
Toxicology
(1991)
A.B. Okey et al.
Toxicol. Lett.
(1994)
A.B. Okey et al.
Trends Pharmacol. Sci.
(1994)
M.S. Denison et al.
J. Biol. Chem.
(1988)
A. Lusska et al.
J. Biol. Chem.
(1993)
M.R. Hsia et al.
Toxicol. Lett.
(1985)
L. Poellinger et al.
Trends Pharmacol. Sci.
(1992)
W. Li et al.
Arch. Biochem. Biophys.
(1994)
C. Esser et al.
Int. J. Immunopharmacol.
(1993)
E.J. Choi et al.
J. Biol. Chem.
(1991)

G.C. Clark et al.

Toxicol. Appl. Pharmacol.

(1991)

D.K. Strom et al.

Arch. Biochem. Biophys.

(1992)

M. Pesonen et al.

Arch. Biochem. Biophys.

(1992)

T. Sawyer et al.

Toxicology

(1986)

D.C. Spink et al.

J. Steroid. Biochem. Mol. Biol.

(1994)

A.K. Jaiswal

J. Biol. Chem.

(1994)

D.W. Nebert et al.

J. Biol. Chem.

(1980)

M.K. Korkalainen et al.

Chem.-Biol. Interact.

(1995)

S.P. Ivy et al.

J. Biol. Chem.

(1988)

P.A. Munzel et al.

Biochem. Pharmacol.

(1994)

D.W. Bombick et al.

Biochem. Biophys. Res. Commun.

(1985)

J.L. Newsted et al.

Toxicol. Appl. Pharmacol.

(1993)

B.U. Stahl et al.

Toxicology

(1993)

C.H. Sewall et al.

Toxicol. Appl. Pharmacol.

(1995)

B. Astroff et al.

Mol. Cell. Endocrinol.

(1990)

Y. Lu et al.

Toxicol. Appl. Pharmacol.

(1994)

M. Romkes et al.

Toxicol. Appl. Pharmacol.

(1987)

M.J. DeVito et al.

Toxicol. Appl. Pharmacol.

(1992)

F.H. Lin et al.

Toxicol. Appl. Pharmacol.

(1991)

K.W. Gaido et al.

Toxicol. Appl. Pharmacol.

(1994)

A.E. Silverstone et al.

Toxicol. Appl. Pharmacol.

(1994)

F.J. Gonzalez et al.

J. Biol. Chem.

(1985)

K. Sogawa et al.

J. Biol. Chem.

(1985)

L.V. Favreau et al.

J. Biol. Chem.

(1991)

A.K. Jaiswal

J. Biol. Chem.

(1994)

H.-C.J. Lai et al.

J. Biol. Chem.

(1988)

E.K.O. Kruithof et al.

Biochem. Biophys. Res. Commun.

(1988)

G. Bensi et al.

Gene

(1987)

S. Takashiba et al.

Gene

(1993)

R. Piva et al.

Biochem. Biophys. Res. Commun.

(1992)

A. Wynshaw-Boris et al.

J. Biol. Chem.

(1984)

D.C. Asman et al.

J. Biol. Chem.

(1993)

L. Roberts

Science

(1991)

T. Reichhardt

Nature

(1994)

A. Poland et al.

Annu. Rev. Pharmacol. Toxicol.

(1982)

L.A. Couture et al.

Teratology

(1990)

J. Huff et al.

Annu. Rev. Pharmacol. Toxicol.

(1994)

C. Esser

Int. Arch. Allergy Immunol.

(1994)

P. Fernandez-Salguero et al.

Science

(1995)

E.C. Hoffman et al.

Science

(1991)

Cited by (93)

Chlorocholine chloride exposure induced spermatogenic dysfunction via iron overload caused by AhR/PERK axis-dependent ferritinophagy activation
2024, Ecotoxicology and Environmental Safety
Chlorocholine chloride (CCC) is a plant growth regulator used worldwide that is detectable in cereals, fruits and animal products. The health effects of CCC exposure have raised public concern. Our previous research showed that CCC exposure decreased testosterone synthesis in pubertal rats. However, little is known about whether and how pubertal CCC exposure impacts spermatogenesis. In this study, we used BALB/c mice and spermatogonia-derived GC-1 cells to examine CCC-induced spermatogenic dysfunction. In vivo, pubertal CCC exposure led to decreased testicular weight, decreased testicular germ cells and poor sperm quality. This effect worsened after cessation of CCC exposure for the next 30 days. RNA-seq and western blot analysis revealed that CCC induced aryl hydrocarbon receptor (AhR) signaling, endoplasmic reticulum stress (ERS) and ferritinophagy. Increased iron content and lipid peroxidation levels were also observed in CCC-treated testes. In vitro, it was identified that iron overload mediated by enhanced ferritinophagy occurred in CCC-treated GC-1 cells, which might be attributed to the PERK pathway in ERS. Further, for the first time, our study elucidated the involvement of AhR in CCC-induced iron overload, which aggravated testicular oxidative damage via lipid peroxidation. Considering the adverse impact of CCC exposure on rodents, supportive evidence from GC-1 cells, and the critical importance of spermatogenesis on male development, the effects of CCC on the male reproduction warrant increased attention.
Acute 2,3,7,8-Tetrachlorodibenzo-p-dioxin exposure in adult mice does not alter the morphology or inflammatory response of cortical microglia
2021, Neuroscience Letters
Citation Excerpt :
AhR is a ubiquitously expressed ligand-activated transcription factor which monitors environmental cues and sends physiological signals that permit normal cellular function by regulating a large number of intracellular processes [4,5]. Subsequently, when TCDD activates this receptor, a cascade of negative responses can be induced, including increased expression of metabolic enzymes and inflammatory factors [6,7]. While TCDD is known to be neurotoxic [8,9], the cellular pathways through which TCDD and other dioxins affect brain function are still unclear.
Microglia, the immune cells of the brain, have a canonical role in regulating responses to neurological disease or injury, but have also recently been implicated as regulators of neurophysiological processes such as learning and memory. Given these dual immune and physiological roles, microglia are a likely mechanism by which external toxic stimuli are converted into deficits in neuronal circuitry and subsequently function. However, while it is well established that exposure to environmental toxicants negatively affects the peripheral immune system, it remains unknown whether and how such exposure causes neuroinflammation which, in turn, may negatively impact microglial functions in vivo. Here, we examined how acute 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in adulthood, which negatively impacts immune cells in the periphery, affects microglial characteristics in the cortex of the mouse. We found that microglia density, distribution, morphology, inflammatory signaling, and response to a secondary, pathological activation were unaffected by acute TCDD exposure. These results suggest that acute, peripheral TCDD exposure in adulthood is not sufficient to induce an overt inflammatory phenotype in cortical microglia.
Aryl hydrocarbon receptor-dependent apoptotic cell death induced by the flavonoid chrysin in human colorectal cancer cells
2016, Cancer Letters
Citation Excerpt :
The mechanism of AHR-dependent regulation of Tnfα and Tnfβ gene expression has not been elucidated. The proximal −1 kb promoter region of human Tnfα gene does not reveal an AHR-binding DRE sequence [39]. In contrast to the Tnfα gene, the human Tnfβ gene has one copy of core sequence of DRE (5′-GCGTG-3′ or 5′-CACTG-3′) on distal, proximal and downstream promoter regions (distal: −1079 to −1074, proximal: −59 to −54, downstream: +399 to +404) [40].
The polyphenolic flavone chrysin has been evaluated as a natural chemopreventive agent due to its anti-cancer effects in a variety of cancer cell lines. However, the mechanism of the chemopreventive effect has been not well established, especially in human colorectal cancer cells. We evaluated the chemopreventive effect of chrysin in three different human colorectal cancer cell lines. We found that chrysin treatment consequently reduced cell viability via induction of apoptosis. We identified that the involvement of up-regulation of pro-apoptotic cytokines tumor necrosis factor (Tnf) α and β genes and consequent activation of the TNF-mediated transcriptional pathway in chrysin-induced apoptosis. Using our generated AHR siRNA expressing colorectal cancer cells, we demonstrated that the chrysin-induced up-regulation of Tnfα and β gene expression was dependent on the aryl hydrocarbon receptor (AHR), which is a ligand–receptor for chrysin. Subsequently, we found that the AHR siRNA expressing colorectal cancer cells were resistant to chrysin-induced apoptosis. Therefore, we concluded that AHR is required for the chrysin-induced apoptosis and the up-regulation of Tnfα and β gene expression in human colorectal cancer cells.
Gene-chemical interactions in the developing mammalian nervous system: Effects on proliferation, neurogenesis and differentiation
2010, NeuroToxicology
The orderly formation of the nervous system requires a multitude of complex, integrated and simultaneously occurring processes. Neural progenitor cells expand through proliferation, commit to different cell fates, exit the cell cycle, generate different neuronal and glial cell types, and new neurons migrate to specified areas and establish synaptic connections. Gestational and perinatal exposure to environmental toxicants, pharmacological agents and drugs of abuse produce immediate, persistent or late-onset alterations in behavioral, cognitive, sensory and/or motor functions. These alterations reflect the disruption of the underlying processes of CNS formation and development. To determine the neurotoxic mechanisms that underlie these deficits it is necessary to analyze and dissect the complex molecular processes that occur during the proliferation, neurogenesis and differentiation of cells. This symposium will provide a framework for understanding the orchestrated events of neurogenesis, the coordination of proliferation and cell fate specification by selected genes, and the effects of well-known neurotoxicants on neurogenesis in the retina, hippocampus and cerebellum. These three tissues share common developmental profiles, mediate diverse neuronal activities and function, and thus provide important substrates for analysis. This paper summarizes four invited talks that were presented at the 12th International Neurotoxicology Association meeting held in Jerusalem, Israel during the summer of 2009. Donald A. Fox described the structural and functional alterations following low-level gestational lead exposure in children and rodents that produced a supernormal electroretinogram and selective increases in neurogenesis and cell proliferation of late-born retinal neurons (rod photoreceptors and bipolar cells), but not Müller glia cells, in mice. Lisa Opanashuk discussed how dioxin [TCDD] binding to the arylhydrocarbon receptor [AhR], a transcription factor that regulates xenobiotic metabolizing enzymes and growth factors, increased granule cell formation and apoptosis in the developing mouse cerebellum. Alex Zharkovsky described how postnatal early postnatal lead exposure decreased cell proliferation, neurogenesis and gene expression in the dentate gyrus of the adult hippocampus and its resultant behavioral effects. Bernard Weiss illustrated how environmental endocrine disruptors produced age- and sex-dependent alterations in synaptogenesis and cognitive behavior.
The pleiotropy of dioxin toxicity - Xenobiotic misappropriation of the aryl hydrocarbon receptor's alternative physiological roles
2009, Pharmacology and Therapeutics
Citation Excerpt :
Further involvement of AhR in immune function is informed by studies from the Esser lab focused on AhR target genes, whose expression has been implicated in differentiation of immature T cells. They reasoned that, as T cell differentiation was largely controlled by cytokines, and, as many cytokine gene promoters were found to contain potential XREs (Lai et al., 1996), a thorough analysis of cytokine levels in immature T cells may reveal AhR regulation of T-cell maturation (Lai et al., 1997). From this study, mRNA of several cytokines including IL-1β, IL-2 (cytotoxic T and Treg differentiation) and TNF-α were upregulated by treatment with TCDD.
The aryl hydrocarbon receptor is a signal regulated transcription factor that has best been characterised as regulating the xenobiotic response to a variety of planar aromatic hydrocarbons. There is compelling evidence that it mediates most, if not all, of the toxic effects of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin). Dioxin exposure results in a wide variety of toxic outcomes including severe wasting syndrome, chloracne, thymic involution, severe immune suppression, reduced fertility, hepatotoxicity, teratogenicity, tumour promotion and death. The pleiotropy of toxic outcomes implies the disruption of a wide range of normal physiological functions. The aryl hydrocarbon receptor has developmentally restricted expression as well as developmental defects in gene-targeted mice. It has a wide range of target genes that do not fit into the classical xenobiotic metabolising gene battery and has recently been shown to interact with NF-kappa B and the estrogen receptor. There is also evidence for its activation in the absence of exogenous ligand, all of which point to various roles outside xenobiotic metabolism. Ligands so far identified display differential activation potential with respect to receptor activity. This article addresses activities of the aryl hydrocarbon receptor that are outside the xenobiotic response. Known physiological roles are discussed as well as how their disruption contributes to the pleiotropic toxicity of TCDD.
TCDD exposure disrupts mammary epithelial cell differentiation and function
2009, Reproductive Toxicology
Mammary gland growth and differentiation during pregnancy is a developmental process that is sensitive to the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD is a widespread environmental contaminant and a potent ligand for the aryl hydrocarbon receptor (AhR). We demonstrate reduced β-casein protein induction in mouse mammary glands and in cultured SCp2 mammary epithelial cells following exposure to TCDD. SCp2 cells exposed to TCDD also show reduced cell clustering and less alveolar-like structure formation. SCp2 cells express transcriptionally active AhR, and exposure to TCDD induces expression of the AhR target gene CYP1B1. Exposure to TCDD during pregnancy reduced expression of the cell adhesion molecule E-cadherin in the mammary gland and decreased phosphorylation of STAT5, a known regulator of β-casein gene expression. These data provide morphological and molecular evidence that TCDD-mediated AhR activation disrupts structural and functional differentiation of the mammary gland, and present an in vitro model for studying the effects of TCDD on mammary epithelial cell function.

View all citing articles on Scopus

View full text

Review articleIdentification of dioxin-responsive elements (DREs) in the 5′ regions of putative dioxin-inducible genes

Abstract

Toxicology

Toxicol. Lett.

Trends Pharmacol. Sci.

J. Biol. Chem.

J. Biol. Chem.

Toxicol. Lett.

Trends Pharmacol. Sci.

Arch. Biochem. Biophys.

Int. J. Immunopharmacol.

J. Biol. Chem.

Toxicol. Appl. Pharmacol.

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

Toxicology

J. Steroid. Biochem. Mol. Biol.

J. Biol. Chem.

J. Biol. Chem.

Chem.-Biol. Interact.

J. Biol. Chem.

Biochem. Pharmacol.

Biochem. Biophys. Res. Commun.

Toxicol. Appl. Pharmacol.

Toxicology

Toxicol. Appl. Pharmacol.

Mol. Cell. Endocrinol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Gene

Gene

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Science

Nature

Annu. Rev. Pharmacol. Toxicol.

Teratology

Annu. Rev. Pharmacol. Toxicol.

Int. Arch. Allergy Immunol.

Science

Science

Review article
Identification of dioxin-responsive elements (DREs) in the 5′ regions of putative dioxin-inducible genes