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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant which elicits a wide range of toxic responses. The developing male rat reproductive system is 100 times more sensitive to TCDD than is its adult counterpart. In utero and lactational exposure to a single low dose delays testis descent and preputial separation, decreases testis, epididymis, and accessory sex organ weights, and decreases daily sperm production, epididymal sperm reserves, and ejaculated sperm numbers throughout development. The mechanism underlying the spectrum of toxic responses elicited by TCDD is poorly understood. TCDD binds the aryl hydrocarbon receptor (AhR), which translocates to the nucleus and dimerizes with the AhR nuclear translocator (ARNT). This complex, a ligand-activated transcription factor, binds to enhancer elements (DREs) in the 5' regulatory region of genes and activates transcription. Although none of the TCDD-responsive genes identified to date have been directly linked to toxicity, it is thought that induction or repression of transcription of genes which have not yet been identified may play a key role in eliciting toxic responses. To better understand the mechanism by which TCDD selectively impairs the developing male reproductive system, we are characterizing the ontogeny and distribution of the AhR and ARNT within this organ system. In addition, we are working to identify genes that are transcriptionally modulated by in utero and lactational TCDD exposure in the prostate and epididymis, two organs which are particularly sensitive to this treatment. The identification of a TCDD-responsive gene(s) with known function may provide insight into the mechanism by which TCDD affects growth and/or function of the prostate, epididymis, and perhaps other organs as well. Novel genes will require characterization before mechanistic hypotheses can be formulated.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant which elicits a wide range of toxic responses. The developing male rat reproductive system is 100 times more sensitive to TCDD than is its adult counterpart. In utero and lactational exposure to a single low dose delays testis descent and preputial separation, decreases testis, epididymis, and accessory sex organ weights, and decreases daily sperm production, epididymal sperm reserves, and ejaculated sperm numbers throughout development. The mechanism underlying the spectrum of toxic responses elicited by TCDD is poorly understood. TCDD binds the aryl hydrocarbon receptor (AhR), which translocates to the nucleus and dimerizes with the AhR nuclear translocator (ARNT). This complex, a ligand-activated transcription factor, binds to enhancer elements (DREs) in the 5' regulatory region of genes and activates transcription. Although none of the TCDD-responsive genes identified to date have been directly linked to toxicity, it is thought that induction or repression of transcription of genes which have not yet been identified may play a key role in eliciting toxic responses. To better understand the mechanism by which TCDD selectively impairs the developing male reproductive system, we are characterizing the ontogeny and distribution of the AhR and ARNT within this organ system. In addition, we are working to identify genes that are transcriptionally modulated by in utero and lactational TCDD exposure in the prostate and epididymis, two organs which are particularly sensitive to this treatment. The identification of a TCDD-responsive gene(s) with known function may provide insight into the mechanism by which TCDD affects growth and/or function of the prostate, epididymis, and perhaps other organs as well. Novel genes will require characterization before mechanistic hypotheses can be formulated.
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Michael DeVito,Bas Bokkers,Majorie B. M. van Duursen,Karin van Ede,Mark Feeley, Elsa Antunes Fernandes Gaspar,Laurie Haws,Sean Kennedy,Richard E. Peterson,Ron Hoogenboom,Keiko Nohara, Kim Petersen,
REGULATORY TOXICOLOGY AND PHARMACOLOGY (2024): 105525-105525
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