TY - JOUR
T1 - Aryl-hydrocarbon receptor-dependent pathway and toxic effects of TCDD in humans
T2 - A population-based study in Seveso, Italy
AU - Baccarelli, Andrea
AU - Pesatori, Angela C.
AU - Masten, Scott A.
AU - Patterson, Donald G.
AU - Needham, Larry L.
AU - Mocarelli, Paolo
AU - Caporaso, Neil E.
AU - Consonni, Dario
AU - Grassman, Jean A.
AU - Bertazzi, Pier Alberto
AU - Landi, Maria Teresa
PY - 2004/4/1
Y1 - 2004/4/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.toxlet.2003.12.062
DO - 10.1016/j.toxlet.2003.12.062
M3 - Article
C2 - 15093275
AN - SCOPUS:11144357329
SN - 0378-4274
VL - 149
SP - 287
EP - 293
JO - Toxicology Letters
JF - Toxicology Letters
IS - 1-3
ER -