Project: Blood cell PAH-DNA adducts and lung cancer risk. Xuan Wei, in southern China, has the highest lung cancer rates in the country, and the etiologic cause is considered to be exposure to smoky coal, used for heating and cooking.
The aim of this study is to elucidate the interaction between environmental exposure and etiology of lung cancer among women in Xuan Wei by measuring leukocyte PAH-DNA damage as a biomarker associated with increased risk of disease. The epidemiological analysis is currently in progress. Carcinogenic polycyclic aromatic hydrocarbons (PAHs) were disposed directly into the Saguenay River of the St. Lawrence Estuary (SLE) by local aluminum smelters (Quebec, Canada) for 50 years (1926 to 1976). PAHs in the river sediments are likely etiologically related to gastrointestinal epithelial cancers observed in 7% of 156 mature (19 year old) adult beluga found dead along the shorelines. Because DNA adduct formation provides a critical link between exposure and cancer induction, and because PAH-DNA adducts are chemically stable, we hypothesized that SLE beluga intestine would contain PAH-DNA adducts. Using an antiserum specific for DNA modified with several carcinogenic PAHs, we stained sections of paraffin-embedded intestine from 51 SLE beluga (0-63 yr), 4 Cook Inlet (CI) Alaska beluga (0-26 yr), and 20 beluga (0-46 yr) living in Arctic areas (Eastern Beaufort Sea, Eastern Chukchi Sea, Point Lay Alaska) and aquaria, all with low PAH contamination. Stained sections showed nuclear light-to-dark pink color indicating the presence of PAH-DNA adducts concentrated in intestinal crypt epithelial lining cells. Scoring of whole tissue sections revealed higher values for the 51 SLE beluga, compared with the 20 Arctic and aquarium beluga (p=0.003). The H-scoring system, applied to coded individual photomicrographs, confirmed that SLE beluga and CI beluga had levels of intestinal PAH-DNA adducts significantly higher than Arctic and aquarium beluga (p = 0.003 and 0.02, respectively). Furthermore, high levels of intestinal PAH-DNA adducts in 4 SLE beluga with gastrointestinal cancers, considered as a group, support a link of causality between PAH exposure and intestinal cancer in SLE beluga. A manuscript has been submitted to Environmental and Molecular Mutagenesis. Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) widely used for adjuvant therapy of breast cancer. An important side-effect of TAM is increased risk of endometrial cancer. To investigate mechanisms underlying this effect we examined transcriptional and epigenetic changes in human and monkey uterus, normal human mammary epithelial cells (NHMECs), and human endometrial stromal cells (HESCs). Uterine DNA from women (n=9), Erythrocebus patas monkeys (n=3), and Macaca fascicularis monkeys (n=6), all exposed to TAM, showed no difference in 5-methyl-cytosine (5-meC) levels compared to unexposed controls (n=6, 2, and 6, respectively). Microarray comparison of TAM-exposed and unexposed NHMECs and HESCs revealed cell-specific differences, with confirmation by RT-PCR. TAM-exposed NHMECs showed up-regulation of interferon signaling and immune response pathways, while TAM-exposed HESCs showed up-regulation of steroid and fatty acid biosynthesis pathways. Promoter region CpG islands for genes highly up-regulated by TAM in NHMECs (MX1 and STAT1) and in HESCs (PPARG, SREBF2, HMCGS and Prune2), did not show significant differences for 5-meC. We did observe a significant depletion of total histone H3, and dimethyl histone H3 lysines K4, K27 and K36, by Western blot, in TAM-exposed HESCs, compared to unexposed controls. Whereas TAM exposure had no discernible effect on 5-meC levels in primate uterus, TAM induced up-regulation of different transcriptional pathways in NHMECs and HESCs, and concomitantly depleted some H3 dimethyl histone lysine levels in HESCs. These findings highlight several features of transcriptional dysregulation by TAM that shouldbe further investigated in the context of TAM-induced endometrial carcinogenesis. A manuscript is in progress.
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