The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and member of the bHLH/PAS (basic Helix-Loop-Helix/Per-Arnt-Sim) family of chemosensors and developmental regulators. It represents a multifunctional molecular switch regulating endo- and xenobiotic metabolism as well as cell proliferation and differentiation. Physiologic functions of the AhR are beginning to be understood, including functions in vascular development, and in detoxification of endo- and xenobiotics. The AhR is also recognized as the culprit for most toxic responses observed after exposure to dioxins and related compounds such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The non-metabolizable AhR agonist TCDD has to be distinguished from the myriad of metabolizable agonists present as dietary contaminants and plant constituents as well as endogenous toxins. The hypothesis is emerging that the diverse tissue-specific, TCDD-mediated toxicities are due to sustained and inappropriate AhR activation leading to deregulated physiologic functions. In support of this hypothesis recent observations in the context of some TCDD-mediated toxic responses are discussed, such as chloracne, cleft palate, thymus involution and in particular carcinogenesis. Major open questions are addressed, such as ligand-independent AhR activation by phosphorylation and the large differences in species-dependent susceptibility to toxic responses. Though important issues remain unresolved, the commentary is intended to stimulate efforts to understand dioxin-mediated toxic responses with emphasis on carcinogenesis in comparison with AhR-mediated physiologic functions.
"AhR is a ligand-dependent transcription factor that has been shown to regulate numerous biological processes including cellular response to xenobiotics (Bock and Kohle, 2006). The expression of CYP1A1 is routinely used as an indicator of the activation of the AhR-signaling pathways. "
"PCB126 also significantly increased the mRNA level of the AhR in the liver. Sustained AhR activation is believed to be the mechanism of the many negative health effects of dioxin like compounds  . Implant studies with lower doses of PCB126 or other AhR agonists may be a useful tool to further explore the long term consequences of low dose exposure to these compounds via food, air or water and possible intervention strategies with antagonists like resveratrol. "
[Show abstract][Hide abstract] ABSTRACT: A new delivery method via polymeric implants was used for continuous exposure to PCBs. Female Sprague-Dawley rats received subcutaneous polymeric implants containing PCB126 (0.15% load), PCB153 (5% load), or both, for up to 45 days and release kinetics and tissue distribution were measured. PCB153 tissue levels on day 15 were readily detected in lung, liver, mammary and serum, with highest levels in the mammary tissue. PCB126 was detected only in liver and mammary tissues. However, a completely different pharmacokinetics was observed on co-exposure of PCB153 and PCB126, with a 1.8-fold higher levels of PCB153 in the liver whereas a 1.7-fold lower levels in the mammary tissue. PCB126 and PCB153 caused an increase in expression of key PCB-inducible enzymes, CYP 1A1/2 and 2B1/2, respectively. Serum and liver activities of the antioxidant enzymes, PON1 and PON3, and AhR transcription were also significantly increased by PCB126. (32) P-Postlabeling for polar and lipophilic DNA-adducts showed significant quantitative differences: PCB126 increased 8-oxodG, an oxidative DNA lesion, in liver and lung tissues. Adduct levels in the liver remained upregulated up to 45 days, while some lung DNA adducts declined. This is the first demonstration that continuous low-dose exposure to PCBs via implants can produce sustained tissue levels leading to the accumulation of DNA-adducts in target tissue and induction of indicator enzymes. Collectively, these data demonstrate that this exposure model is a promising tool for long-term exposure studies.
[Show abstract][Hide abstract] ABSTRACT: Alkylated polycyclic aromatic hydrocarbons (alkyl-PAHs) are the predominant form of PAHs in oil, comprising 85–95% of total PAHs. However, little attention has been paid to these chemicals in ecological risk assessment of marine oil spill. A comparative study of the toxic effects of phenanthrene and retene (7-isopropyl-1-methylphenanthrene, an alkyl-phenanthrene) on the early life stage of marine medaka (Oryzias melastigma) was conducted. Results showed that retene was significantly more toxic than phenanthrene, and marine medaka could be more sensitive to retene than some freshwater fishes. Retene had a higher excretion rate than phenanthrene during the larvae stage. Both of compounds resulted in developmental malformation of marine medaka embryos, with phenanthrene affecting on peripheral vascular system and yolk sac, while retene affecting on cardiac tissues. The toxicity of phenanthrene might be mainly related to its anesthetic effects, and that of retene might be related to the CYP1A-mediated toxicity of its metabolites.
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