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 ³²P-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.
Section for Toxicology, Department of Chemical and Biological Working Environment, National Institute of Occupational Health, Oslo, Norway.
Heidi
H
Uppstad
Gro Helene
GH
Osnes
Kathleen J
KJ
Cole
David H
DH
Phillips
Aage
A
Haugen
Steen
S
Mollerup
D000230:Adenocarcinoma / Q000503:physiopathology; D000077192:Adenocarcinoma of Lung; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D018736:DNA Adducts / Q000378:metabolism; D004198:Disease Susceptibility; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000503:physiopathology; D008297:Male; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D013638:Tars / Q000378:metabolism
D002273:Carcinogens; D018736:DNA Adducts; D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; D012097:Repressor Proteins; D013638:Tars; C024746:tobacco tar; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001564:Benzo(a)pyrene; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1