Biotransformation of Benzo[a]pyrene in Ahr Knockout Mice Is Dependent on Time and Route of Exposure

Benzo[a]pyrene (BP) is an ubiquitous environmental pollutant with potent mutagenic and carcinogenic properties. The Ah receptor (Ahr) is important in the metabolic activation of BP and is therefore central to BP-induced carcinogenesis. Although Ahr(-/-) mice are refractory to BP-induced carcinogenesis, higher levels of BP-DNA and -protein adducts were formed in them than in wild-type mice. These results indicated the presence of an Ahr-independent and/or a slower biotransformation of BP in Ahr knockout mice. To address this issue further, we have now performed a time-course experiment, with mice receiving a single oral dose of BP (100 mg/kg). Wild-type mice have an effective clearance of BP metabolites, mainly through 3-hydroxybenzo[a]pyrene and 9-hydroxybenzo[a]pyrene in the feces with reduced levels of DNA and protein adducts in the examined tissues. On the other hand, the Ahr(-/-) mice appear to have a lower metabolic clearance of BP resulting in increased levels of DNA and protein adducts and of unmetabolized BP. In addition, we have performed an administration route experiment and found that skin-exposed Ahr(-/-) mice showed lower levels of protein adducts along with markedly reduced P450 1B1 expression, but only in the exposed area, as compared with the wild-type mice. In addition, the systemic uptake of BP is increased in the Ahr(-/-) mice as compared with the wild-type mice. Hence, the lack of a functional Ah receptor results in an Ahr-independent biotransformation of BP with a slower clearance of BP and higher levels of DNA and protein adducts, but the distribution and levels of BP and BP-protein adducts are clearly dependent on the route of exposure

Sex differences in susceptibility to PAHs is an intrinsic property of human lung adenocarcinoma cells

Recent epidemiological studies have disputed whether females are at increased risk of lung cancer compared to males. However, several molecular studies are in support of an increased susceptibility to tobacco smoke carcinogens among females. Our earlier findings suggest that women display higher levels of smoking-induced bulky/hydrophobic DNA adducts which may be related to an increased expression of CYP1A1 in their lungs, compared to men. In this in vitro study, 11 lung adenocarcinoma cell lines, 6 of male and 5 of female origin, were exposed to benzo[a]pyrene, cigarette smoke condensate (CSC), or vehicle control. Subsequent expression analysis of genes in the polycyclic aromatic hydrocarbon bioactivation pathway was conducted with Real-Time RT-PCR. DNA adducts were measured in benzo[a]pyrene-exposed cells by P-32-postlabelling analysis, and CYP1 activity was measured by EROD assay. Analysis of benzo[a]pyrene-DNA adducts showed higher levels of adducts in cell lines from women compared to cell lines from men (p = 0.03). The results also revealed significant sex differences in CYP1A1 gene expression, both in untreated cells (p = 0.03), and in cells exposed to benzo[a]pyrene (p = 0.017) and cigarette smoke condensate (p = 0.0043). In CSC-exposed cells, significantly higher levels of CYP1 activity was found in cell lines of female origin (p = 0.049). These results are in support of the previously published in vivo data, providing evidence for a higher susceptibility to PAH of women's lungs. (C) 2010 Elsevier Ireland Ltd. All rights reserved

Timed written picture naming in 14 European languages

We describe the Multilanguage Written Picture Naming Dataset. This gives trial-level data and time and agreement norms for written naming of the 260 pictures of everyday objects that compose the colorized Snodgrass and Vanderwart picture set (Rossion & Pourtois in Perception, 33, 217–236, 2004). Adult participants gave keyboarded responses in their first language under controlled experimental conditions (N = 1,274, with subsamples responding in Bulgarian, Dutch, English, Finnish, French, German, Greek, Icelandic, Italian, Norwegian, Portuguese, Russian, Spanish, and Swedish). We measured the time to initiate a response (RT) and interkeypress intervals, and calculated measures of name and spelling agreement. There was a tendency across all languages for quicker RTs to pictures with higher familiarity, image agreement, and name frequency, and with higher name agreement. Effects of spelling agreement and effects on output rates after writing onset were present in some, but not all, languages. Written naming therefore shows name retrieval effects that are similar to those found in speech, but our findings suggest the need for cross-language comparisons as we seek to understand the orthographic retrieval and/or assembly processes that are specific to written output

Inflammation-associated extracellular β-glucuronidase alters cellular responses to the chemical carcinogen benzo[a]pyrene

Neutrophils infiltrate tissues during inflammation, and when activated, they release β-glucuronidase. Since inflammation is associated with carcinogenesis, we investigated how extracellular β-glucuronidase changed the in vitro cellular response to the chemical carcinogen benzo(a)pyrene (B[a]P). For this we exposed human liver (HepG2) and lung (A549) cells to B[a]P in the presence or absence of β-glucuronidase. β-Glucuronidase reduced B[a]P-induced expression of CYP1A1 and CYP1B1 at 6 h after exposure, which did not depend on β-glucuronidase activity, because the inhibitor d-saccharic acid 1,4-lactone monohydrate did not antagonize the effect of β-glucuronidase. On the other hand, the inhibitory effect of β-glucuronidase on CYP expression was dependent on signalling via the insulin-like growth factor receptor (IGF2R, a known receptor for β-glucuronidase), because co-incubation with the IGF2R inhibitor mannose-6-phosphate completely abolished the effect of β-glucuronidase. Extracellular β-glucuronidase also reduced the formation of several B[a]P metabolites and B[a]P–DNA adducts. Interestingly, at 24 h of exposure, β-glucuronidase significantly enhanced CYP expression, probably because β-glucuronidase de-glucuronidated B[a]P metabolites, which continued to trigger the aryl hydrocarbon receptor (Ah receptor) and induced expression of CYP1A1 (in both cell lines) and CYP1B1 (in A549 only). Consequently, significantly higher concentrations of B[a]P metabolites and DNA adducts were found in β-glucuronidase-treated cells at 24 h. DNA adduct levels peaked at 48 h in cells that were exposed to B[a]P and treated with β-glucuronidase. Overall, these data show that β-glucuronidase alters the cellular response to B[a]P and ultimately enhances B[a]P-induced DNA adduct levels