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

• Published in: Toxicology letters Vol. 149; no. 1; pp. 287 - 293
• Main Authors: Baccarelli, Andrea, Pesatori, Angela C, Masten, Scott A, Patterson, Donald G, Needham, Larry L, Mocarelli, Paolo, Caporaso, Neil E, Consonni, Dario, Grassman, Jean A, Bertazzi, Pier Alberto, Landi, Maria Teresa
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Shannon Elsevier Ireland Ltd 01.04.2004; Amsterdam Elsevier Science
• Subjects: Adult; Aged; Analysis. Health state; Aryl Hydrocarbon Hydroxylases - biosynthesis; Aryl Hydrocarbon Receptor Nuclear Translocator; Aryl-hydrocarbon receptor; Biological and medical sciences; Biomarkers; Body Burden; Chemical and industrial products toxicology. Toxic occupational diseases; Complement C3 - analysis; Complement C4 - analysis; Cytochrome P-450 CYP1A1 - biosynthesis; Cytochrome P-450 CYP1A1 - metabolism; Cytochrome P-450 CYP1B1; Dioxin; DNA-Binding Proteins; Environmental Pollutants - toxicity; Epidemiology; Female; General aspects; Humans; Immunoglobulins - analysis; In Vitro Techniques; Italy - epidemiology; Lymphocytes - enzymology; Male; Medical sciences; Middle Aged; Molecular epidemiology; Polychlorinated Dibenzodioxins - toxicity; Population; Population-based study; Public health. Hygiene; Public health. Hygiene-occupational medicine; Receptors, Aryl Hydrocarbon - biosynthesis; Receptors, Aryl Hydrocarbon - physiology; RNA, Messenger - analysis; RNA, Messenger - biosynthesis; TCDD; Toxicology; Transcription Factors - biosynthesis; Various organic compounds; Italy; Europe; TCDD; Molecular epidemiology; Population-based study; Dioxin; Aryl-hydrocarbon receptor; Human; Toxicity; Biological marker; Gene expression; Pollutant; Ah receptor; Chlorine Organic compounds; Public health
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2003.12.062

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 90 ng/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 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. 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.