Photoaffinity labelling of the Ah receptor

Poland, Alan; Glover, Edward; Ebetino, H.; Kende, and A. S.

doi:10.1016/0278-6915(86)90186-9

Cited by 70 publications

(84 citation statements)

References 7 publications

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“…However, consistently high levels of benzo[a]pyreneinduced SCE in embryos of strains high in repair capacity (C57BL/6) or low in repair capacity (BALB/c) (8) (35,36). This concept is based primarily on the extreme toxicity and teratogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which binds specifically to the receptor product of the Ah locus (3,37,38) and leads to cleft palate and other defects in Ah-responsive mice (39,40). Even though cytochrome P-450 induction is a major consequence of TCDD exposure in Ah-responsive mice, enzymes controlled by the Ah receptor are not necessarily responsible for the effects of TCDD; rather, persistent occupation of the Ah receptor itself could interfere with essential cellular regulatory events within the developing embryo or fetus, as postulated by Poland et al (35).…”

Section: Resultsmentioning

confidence: 99%

Cytochrome P-450 metabolic activity in embryonic and extraembryonic tissue lineages of mouse embryos.

Pedersen¹,

Meneses²,

Spindle³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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Mouse morulae, blastocysts, and embryonic and extraembryonic tissue layers were examined for benzo[aJpyrene metabolism by cytochrome P-450, using the sister chromatid exchange assay. Benzo[alpyrene exposure in vitro increased sister chromatid exchanges in blastocysts of all genetically responsive mice examined [BALB/cDub, C3H/AnfCum, and outbred Dub:(ICR) strains] but not blastocysts of the nonresponsive AKR/J strain. Benzo[alpyrene treatment of responsive 71/2-and 81/2-day (postimplantation-stage) embryos, either intact or as separate tissue layers, increased sister chromatid exchanges in tissues of both embryonic and extraembryonic lineages-i.e., in the embryo proper, in isolated embryonic ectoderm, and in yolk sac, chorion, extraembryonic ectoderm, and extraembryonic endoderm layers. These results indicate that cytochrome P-450 is active in most or all tissues of the early mammalian embryo. It could metabolize xenobiotic molecules reaching the conceptus near the onset of morphogenesis and organogenesis, or it could have another as yet undefined role in normal development.Benzo[a]pyrene and other polycyclic aromatic hydrocarbons are metabolized in cells by cytochrome P-450 monooxygenases whose synthesis they induce. The degree of inducibility in mice varies among strains: both cytochromes

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Section: Resultsmentioning

confidence: 99%

Cytochrome P-450 metabolic activity in embryonic and extraembryonic tissue lineages of mouse embryos.

Pedersen¹,

Meneses²,

Spindle³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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“…14). TCDD is not a typical estrogen antagonist, however, because it does not compete with estrogen binding to its receptor (15). Instead, TCDD induces three known cytochrome P450 isozymes that hydroxylate 17␤-estradiol, the most biologically potent estrogen, to various catechols (16).…”

Section: Tcddmentioning

confidence: 99%

Estrogen Receptor Reduces CYP1A1 Induction in Cultured Human Endometrial Cells

Ricci¹,

Toscano

Mattingly

et al. 1999

Journal of Biological Chemistry

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“…First they oxidize a variety of polycyclic aromatic hydrocarbons to more polar and excretable forms (39,40). Second, they can serve as inducible sinks for recalcitrant substrates such as dioxin, thus markedly influencing their disposition (41,42). Because this system commonly results in a substrate inducing its own metabolism, we refer to it as an adaptive response pathway (43).…”

Section: Discussionmentioning

confidence: 99%

A Maternal Ahr Null Genotype Sensitizes Embryos to Chemical Teratogenesis

Thomae

Glover

Bradfield

2004

Journal of Biological Chemistry

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The aryl hydrocarbon receptor (encoded by the Ahr locus) is a ligand-activated transcription factor that mediates the toxicology and teratology of 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin). In an effort to understand the role of the maternal compartment in dioxin teratology, we designed a breeding strategy that allowed us to compare the teratogenic response in embryos from Ahr ؊/؊ (null) and Ahr ؉/؉ (wild-type) dams. Using this strategy, we demonstrate that embryos from the Ahr ؊/؊ dams are 5-fold more sensitive to dioxin-induced cleft palate and hydronephrosis as compared with embryos from an Ahr ؉/؉ dam. Moreover, this increased teratogenic sensitivity extends beyond dioxin, because embryos from Ahr ؊/؊ dams exhibited a 9-fold increase in their sensitivity to the fetotoxic effects of the glucocorticoid, dexamethasone. In searching for an explanation for this increased sensitivity, we found that more dioxin and dexamethasone reached the embryos from Ahr ؊/؊ dams as compared with embryos from Ahr ؉/؉ dams. We propose that increased deposition of teratogens/fetotoxicants to the embryonic compartment is the result of porto-systemic shunting and/or blocked P4501A induction in Ahr ؊/؊ dams. In addition to demonstrating the importance of maternal AHR in teratogenesis, these data may have implications that reach beyond the mechanism of action of dioxin. In this regard, the Ahr ؊/؊ mouse may provide a system that allows pharmacological agents and toxicants to be more easily studied in a model where first pass clearance is a significant obstacle.Chemical teratogens can perturb normal mammalian development through direct action on the embryo, indirectly through maternal toxicity, or as the result of a combination of both of these mechanisms. The maternal compartment can afford protection by functioning as a metabolic or physical barrier that reduces embryonic exposure to a given agent (1). The maternal compartment also holds the potential to serve as a site of teratogen bioactivation and may serve to increase the concentrations of active metabolites that directly perturb normal embryonic development (2, 3). Understanding the relative contributions of maternal and embryonic physiology for a given teratogen can be difficult, especially when chemical agents induce a variety of teratogenic end points or display remarkable pharmacological potency.One approach to understanding the relative contributions of the maternal and embryonic physiology is to define these two compartments via their respective genotypes. Such an approach is particularly powerful when working with null alleles that have been generated via gene targeting. In such cases, the dominance order is clear, as is the functional relationship between one or two copies of the wild-type allele. Through appropriate genetic crosses one can then generate informative combinations of maternal and embryonic genotypes that can help identify when maternally or embryonically expressed loci play a differential role in the teratogenic response to a specific chemical (4).Based...

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Photoaffinity labelling of the Ah receptor

Cited by 70 publications

References 7 publications

Cytochrome P-450 metabolic activity in embryonic and extraembryonic tissue lineages of mouse embryos.

Cytochrome P-450 metabolic activity in embryonic and extraembryonic tissue lineages of mouse embryos.

Estrogen Receptor Reduces CYP1A1 Induction in Cultured Human Endometrial Cells

A Maternal Ahr Null Genotype Sensitizes Embryos to Chemical Teratogenesis

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