The structure-dependent effects of heptachlorodibenzofuran isomers in male C57BL/6 mice: Immunotoxicity and monooxygenase enzyme induction

Dickerson, R.; Howie, L.; Davis, D.; Safe, Stephen

doi:10.1016/0272-0590(90)90056-p

Cited by 15 publications

(9 citation statements)

References 35 publications

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“…TCDD-induced enzyme expression and/or activity (AHH, EROD, and Cyp1a1 expression) (Astroff and Safe, 1989; Astroff et al, 1988; Bannister et al, 1989; Harris et al, 1989; Kim et al, 2006), AhR binding (Gasiewicz and Rucci, 1991), ER binding down-regulation (Romkes et al, 1987), and TCDD-induced porphyria (Yao and Safe, 1989), immunotoxicity (Davis and Safe, 1988; Dickerson et al, 1990), cleft palate, and hydronephrosis (Bannister et al, 1989; Biegel et al, 1989) can be antagonized by SAhRMs. More recently, SAhRMS that modulate hematopoietic progenitor expansion (Boitano et al, 2010), repress cytokine-mediated induction of complement factor genes (Murray et al, 2011), antagonize cytokine-mediated inflammatory signaling (Murray et al, 2010), and inhibit tumor growth (Jin et al, 2012; Safe et al, 1999; Yin et al, 2012) in absence of canonical DRE-elicited transcription have also been developed.…”

Section: Discussionmentioning

confidence: 99%

Comparisons of differential gene expression elicited by TCDD, PCB126, βNF, or ICZ in mouse hepatoma Hepa1c1c7 cells and C57BL/6 mouse liver

et al. 2013

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The aryl hydrocarbon receptor (AhR) is a promiscuous receptor activated by structurally diverse synthetic and natural compounds. AhR activation may lead to ligand-specific changes in gene expression despite similarities in mode of action. Therefore, differential gene expression elicited by four structurally diverse, high affinity AhR ligands (2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 10 nM, 30 µg/kg), 3,3′,4,4′,5-pentachlorobiphenyl (PCB126; 100 nM, 300 µg/kg), β-naphthoflavone (βNF; 10 µM, 90 mg/kg), and indolo[3,2-b]carbazole (ICZ; 1 µM)) in mouse Hepa1c1c7 hepatoma cells and C57BL/6 mouse liver samples were compared. A total of 288, 183, 119, and 131 Hepa1c1c7 genes were differentially expressed (|fold-change| ≥ 1.5, P1(t) ≥ 0.9999) by TCDD, βNF, PCB126, and ICZ, respectively. Only ~35% were differentially expressed by all 4 ligands in Hepa1c1c7 cells. In vivo, 661, 479, and 265 hepatic genes were differentially expressed following treatment with TCDD, βNF, and PCB126, respectively. Similar to Hepa1c1c7 cells, ≤34% of gene expression changes were common across all ligands. Principal components analysis identified time-dependent gene expression divergence. Comparisons of ligand-elicited expression between Hepa1c1c7 cells and mouse liver identified only 11 common gene expression changes across all ligands. Although metabolism may explain some ligand-specific gene expression changes, PCB126, βNF, and ICZ also elicited divergent expression compared to TCDD, suggestive of selective AhR modulation.

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Section: Discussionmentioning

confidence: 99%

Comparisons of differential gene expression elicited by TCDD, PCB126, βNF, or ICZ in mouse hepatoma Hepa1c1c7 cells and C57BL/6 mouse liver

et al. 2013

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“…However, at weekly doses of 0.3 ng/kg, no clear-cut change occurred in the total lymphocyte population (110). The ED50 for the suppression of the primary antibody response to sheep red blood cells in mice is consistendy lower than that for the induction of EROD or AHH, markers for the activity of CYPIAJ (75,111 (115). This appears to be associated with the induction of a liver-specific binding protein which has been tentatively identified as cytochrome P4501A2 (116,117).…”

Section: Toxiic Equivalencymentioning

confidence: 99%

The mechanism of dioxin toxicity: relationship to risk assessment.

Birnbaum

1994

Environ Health Perspect

298

147

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Risk characterization involves hazard identification, determination of dose-response relationships, and exposure assessment. Improvement of the risk assessment process requires inclusion of the best available science. Recent findings in the area of dioxin toxicity have led to a major effort to reassess its risk. 2,3,7,, commonly referred to as "dioxin," is the most toxic member of a class of related chemicals including the polyhalogenated dibenzo-p-dioxins, dibenzofurans, biphenyls, naphthalenes, azo-and azoxy-benzenes, whose toxicities can be expressed as fractional equivalencies of TCDD. These chemicals exert their effects through interaction with a specific intracellular protein, the Ah receptor. While binding to the receptor is necessary, it is not sufficient to bring about a chain of events leading to various responses including enzyme induction, immunotoxicity, reproductive and endocrine effects, developmental toxicity, chloracne, tumor promotion, etc. Some of these responses appear to be linear at low doses. Immunotoxicity and effects on the reproductive system appear to be among the most sensitive responses. The Ah receptor functions as a transcriptional enhancer, interacting with a number of other regulatory proteins (heat shock proteins, kinases, translocases, DNA binding species). Interaction with specific base sequences in the DNA appear to be modulated by the presence of other growth factors, hormones, and their receptors as well as other regulatory proteins. Thus, dioxin appears to function as a hormone, initiating a cascade of events that is dependent upon the environment of each cell and tissue. While Ah receptor variants exist, all vertebrates examined have demonstrated such a protein with similar numbers of receptors and binding affinity for TCDD. Most species respond similarly to dioxin and related compounds. While a given species may be an outlier for a given response, it will behave like other animals for other responses. For both in vivo and in vitro end points where animal and human data exist, such as enzyme induction, chloracne, immunotoxicity, developmental toxicity, and cancer, the sensitivity of humans appears similar to that of experimental animals. Current levels of environmental exposure to this class of chemicals may be resulting in subtle responses in populations at special risk such as subsistence fisherman and the developing infant, as well as in the general population. Increased understanding of the mechanism of dioxin's effects as well as elucidation of exposure-dose relationships is leading to the development of a biologically based dose-response model in the ongoing process of incorporating the best science into the risk assessment of TCDD and related compounds.-Environ Health Perspect 102(Suppl 9) 157-167(1994)

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“…The severity of the suppressive effect correlated with the specific binding affinity of the HAR to the ARR, supporting an AHR mediated mechanism. Such a relationship has been shown for various PCB congeners ) and polychlorinated dibenzofurans (Davis & Safe, 1988;Dickerson et al, 1990). That the AHR antagonist alpha-napthoflavone can abrogate both CYPIA enzyme activity and suppression of hemolytic plaques formed is consistent with an AHR-mediated mechanism (Blank et al, 1987).…”

Section: Cell Cycle Disruption the Phosphorylation Cascades Initiatedmentioning

confidence: 69%

Characterization of an aryl hydrocarbon receptor from a cetacean : an approach for assessing contaminant susceptibility in protected species

Jensen¹

2000

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The structure-dependent effects of heptachlorodibenzofuran isomers in male C57BL/6 mice: Immunotoxicity and monooxygenase enzyme induction

Cited by 15 publications

References 35 publications

Comparisons of differential gene expression elicited by TCDD, PCB126, βNF, or ICZ in mouse hepatoma Hepa1c1c7 cells and C57BL/6 mouse liver

Comparisons of differential gene expression elicited by TCDD, PCB126, βNF, or ICZ in mouse hepatoma Hepa1c1c7 cells and C57BL/6 mouse liver

The mechanism of dioxin toxicity: relationship to risk assessment.

Characterization of an aryl hydrocarbon receptor from a cetacean : an approach for assessing contaminant susceptibility in protected species

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