TCDD-mediated alterations in the AhR-dependent pathway in Seveso, Italy, 20 years after the accident.
Approximately 20 years after the Seveso, Italy, accident we conducted a population-based study to evaluate the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on cancer using mechanistically based biomarkers of dioxin response in humans. TCDD toxic effects are mediated by the aryl hydrocarbon receptor (AhR). We studied the AhR-dependent pathway in lymphocytes from 62 subjects randomly sampled from the highest exposed zones and 59 subjects from the surrounding non-contaminated area, frequency matched for age, gender and smoking. To our knowledge, this is the most comprehensive investigation to date designed to evaluate the key genes in the pathway, including AhR, aryl hydrocarbon receptor nuclear translocator, CYP1A1 and CYP1B1 transcripts and CYP1A1-associated 7-ethoxyresorufin O-deethylase (EROD) activity in a population heavily exposed to dioxin. Current lipid-adjusted plasma TCDD concentrations in these subjects ranged from 3.5 to 90 ng/kg (or p.p.t.) and were negatively associated with AhR mRNA in unstimulated peripheral blood mononuclear cells (P = 0.03). When mitogen-induced lymphocytes were cultured with 10 nM TCDD, all AhR-dependent genes were induced 1.2- to 13-fold. In these cells, plasma TCDD was associated with decreased EROD activity. In addition, there was a strong positive correlation between AhR and CYP1A1 expression (P = 0.001) and between AhR and CYP1B1 expression (P = 0.006). CYP1A1 expression was also strongly correlated with EROD activity (P = 0.001). The analysis of the expression of dioxin-inducible genes involved in carcinogenesis may help in determining dose-response relationships for human exposure to dioxin in vivo and in assessing the variability of human response, which may indicate the presence of subjects more susceptible to disease as a result of such exposures.
Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892-7236, USA. landim@mail.nih.gov
Maria Teresa
MT
Landi
Pier Alberto
PA
Bertazzi
Andrea
A
Baccarelli
Dario
D
Consonni
Scott
S
Masten
George
G
Lucier
Paolo
P
Mocarelli
Larry
L
Needham
Neil
N
Caporaso
Jean
J
Grassman
D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001483:Base Sequence; D016022:Case-Control Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D017931:DNA Primers; D004268:DNA-Binding Proteins; D006801:Humans; D007558:Italy; D000072317:Polychlorinated Dibenzodioxins / Q000009:adverse effects*; D012333:RNA, Messenger / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C497396:ARNT protein, human; D017931:DNA Primers; D004268:DNA-Binding Proteins; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1