Consensus toxicity factors (CTFs) were developed as a novel approach to establish toxicity factors for risk assessment of dioxin-like compounds (DLCs). Eighteen polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs), and biphenyls (PCBs) with assigned World Health Organization toxic equivalency factors (WHO-TEFs) and two additional PCBs were screened in 17 human and rodent bioassays to assess their induction of aryl hydrocarbon receptor-related responses. For each bioassay and compound, relative effect potency values (REPs) compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin were calculated and analyzed. The responses in the human and rodent cell bioassays generally differed. Most notably, the human cell models responded only weakly to PCBs, with 3,3',4,4',5-pentachlorobiphenyl (PCB126) being the only PCB that frequently evoked sufficiently strong responses in human cells to permit us to calculate REP values. Calculated REPs for PCB126 were more than 30 times lower than the WHO-TEF value for PCB126. CTFs were calculated using score and loading vectors from a principal component analysis to establish the ranking of the compounds and, by rescaling, also to provide numerical differences between the different congeners corresponding to the TEF scheme. The CTFs were based on rat and human bioassay data and indicated a significant deviation for PCBs but also for certain PCDD/Fs from the WHO-TEF values. The human CTFs for 2,3,4,7,8-pentachlorodibenzofuran, 1,2,3,4,7,8-hexachlorodibenzofuran, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, and 1,2,3,4,7,8,9-heptachlorodibenzofuran were up to 10 times greater than their WHO-TEF values. Quantitative structure-activity relationship models were used to predict CTFs for untested WHO-TEF compounds, suggesting that the WHO-TEF value for 1,2,3,7,8-pentachlorodibenzofuran could be underestimated by an order of magnitude for both human and rodent models. Our results indicate that the CTF approach provides a powerful tool for condensing data from batteries of screening tests using compounds with similar mechanisms of action, which can be used to improve risk assessment of DLCs.
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is known as a mediator of toxic responses. Recently, it was shown that the AhR has dual functions. Besides being a transcription factor, it also possesses an intrinsic E3 ubiquitin ligase function that targets, e.g., the steroid receptors for proteasomal degradation. The aim of this study was to identify the molecular switch that determines whether the AhR acts as a transcription factor or an E3 ubiquitin ligase. To do this, we used the breast cancer cell line MCF7, which expresses a functional estrogen receptor alpha (ER␣) signaling pathway. Our data suggest that aryl hydrocarbon receptor nuclear translocator (ARNT) plays an important role in the modulation of the dual functions of the AhR. ARNT knockdown dramatically impaired the transcriptional activation properties of the ligand-activated AhR but did not affect its E3 ubiquitin ligase function. The availability of ARNT itself is modulated by another basic helix-loop-helix (bHLH)-Per-ARNT-SIM (PAS) protein, the repressor of AhR function (AhRR). MCF7 cells overexpressing the AhRR showed lower ER␣ protein levels, reduced responsiveness to estradiol, and reduced growth rates. Importantly, when these cells were used to produce estrogendependent xenograft tumors in SCID mice, we also observed lower ER␣ protein levels and a reduced tumor mass, implying a tumor-suppressive-like function of the AhR in MCF7 xenograft tumors.KEYWORDS aryl hydrocarbon receptor, molecular switch, E3 ubiquitin ligase, transcription factor, aryl hydrocarbon receptor nuclear translocator, aryl hydrocarbon receptor repressor B asic helix-loop-helix (bHLH)-Per-aryl hydrocarbon receptor (AhR) nuclear translocator (ARNT)-SIM (PAS) proteins function as biological sensors that respond to physiological stimuli and environmental signals to mediate adaptive cellular responses. In general, these proteins form heterodimers that consist of a signal-induced subunit and an unregulated, ubiquitously expressed subunit (1). A member of the family of bHLH-PAS proteins is the AhR. Initially identified by Poland and Knutson (2) as a binding site for planar, nonhalogenated, and halogenated xenobiotics, in particular the highly toxic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the AhR was viewed for a long time as a mediator of xenobiotic-induced toxicity and carcinogenesis. However, mouse knockdown studies have revealed a role for the AhR beyond xenobiotic-induced toxicity and carcinogenesis. For example, the AhR has been shown to be involved in fetal liver development (3), immune cell modulation and differentiation (4-6), and gastrointestinal homeostasis (7, 8). The developmental defects observed in AhR Ϫ/Ϫ mice and the strong conservation of the AhR throughout evolution (for a review, see reference 9)
Neurotransmitters are commonly implicated in host-microbiome communication, yet the molecular mechanisms of this communication remain largely elusive. We present novel evidence linking the gut microbiome to host development and growth via neurotransmitter l- Dopa in Daphnia , the established model species in ecology and evolution.
The host-microbiome interactions are essential for the physiological and ecological performance of the host, yet these interactions are challenging to identify. Neurotransmitters are commonly implicated in these interactions, but we know very little about the mechanisms of their involvement, especially in invertebrates. Here, we report a peripheral Catecholamine (CA) pathway involving the gut microbiome of the model species Daphnia magna. We demonstrate that: (1) tyrosine hydroxylase and dopa decarboxylase enzymes are present in the gut wall; (2) DOPA decarboxylase gene is expressed in the gut by the host, and its expression follows the molt cycle peaking after ecdysis; (3) biologically active L-Dopa, but not Dopamine, is present in the gut lumen; and (4) gut bacteria produce L-Dopa in a concentration-dependent manner when provided L-Tyrosine as a substrate. Impinging on gut bacteria involvement in host physiology and ecologically relevant traits, we suggest L-Dopa as a communication agent in the host-microbiome interactions in daphnids and, possibly, other crustaceans.
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