Aryl-hydrocarbon receptor-dependent pathway and toxic effects of TCDD in humans: A population-based study in Seveso, Italy

Andrea Baccarelli, Angela C. Pesatori, Scott A. Masten, Donald G. Patterson, Larry L. Needham, Paolo Mocarelli, Neil E. Caporaso, Dario Consonni, Jean A. Grassman, Pier Alberto Bertazzi, Maria Teresa Landi

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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 upon immune and mechanistically based biomarkers of dioxin response in humans. TCDD toxic effects are known to be mediated by the aryl-hydrocarbon receptor (AhR). We randomly selected 62 study subjects from the highest exposed zones and 59 from the surrounding non-contaminated area. Current lipid-adjusted plasma TCDD concentrations in these subjects ranged from 3.5 to 90ng/kg (or ppt) and were negatively associated with plasma IgG concentrations (r=-0.35;P=0.0002). The expression of genes in the AhR-dependent pathway, including AhR, aryl-hydrocarbon receptor nuclear translocator (ARNT), CYP1A1, and CYP1B1 transcripts, and the CYP1A1-associated 7-ethoxyresorufin-O- deethylase (EROD) activity was measured in lymphocytes. AhR mRNA levels in uncultured lymphocytes were negatively associated with plasma TCDD (P=0.03). When mitogen-induced lymphocytes were cultured with 10nM TCDD, all AhR-dependent genes were induced 1.2- to 13-fold. In these cells, plasma TCDD was associated with decreased EROD activity. Markers within the AhR pathway were correlated with one another. Our findings suggest the presence of long-term effects in the subjects exposed to TCDD after the Seveso accident.

Original languageEnglish (US)
Pages (from-to)287-293
Number of pages7
JournalToxicology Letters
Issue number1-3
StatePublished - Apr 1 2004

All Science Journal Classification (ASJC) codes

  • Toxicology


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