Journal Article

TCDD-mediated alterations in the AhR-dependent pathway in Seveso, Italy, 20 years after the accident

Maria Teresa Landi, Pier Alberto Bertazzi, Andrea Baccarelli, Dario Consonni, Scott Masten, George Lucier, Paolo Mocarelli, Larry Needham, Neil Caporaso and Jean Grassman

in Carcinogenesis

Volume 24, issue 4, pages 673-680
Published in print April 2003 | ISSN: 0143-3334
Published online April 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgg002
TCDD-mediated alterations in the AhR-dependent pathway in Seveso, Italy, 20 years after the accident

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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.

Keywords: AhR, aryl hydrocarbon receptor; ARNT, aryl hydrocarbon receptor nuclear translocator; BMI, body mass index; CI, confidence interval; EROD, 7-ethoxyresorufin O-deethylase; FBS, fetal bovine serum; HBSS, Hank's balanced salt solution; IS, internal standard; PBS, phosphate-buffered saline; p.p.t., parts per trillion; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEF, toxic equivalency factor; TEQ, toxic equivalent.

Journal Article.  7042 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

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