Aryl-hydrocarbon receptor-dependent pathway and toxic effects of TCDD in humans: a population-based study in Seveso, Italy.
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 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.
Baccarelli
Andrea
A
Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD 20892-7236, USA. baccarea@mail.nih.gov
Pesatori
Angela C
AC
Masten
Scott A
SA
Patterson
Donald G
DG
Needham
Larry L
LL
Mocarelli
Paolo
P
Caporaso
Neil E
NE
Consonni
Dario
D
Grassman
Jean A
JA
Bertazzi
Pier Alberto
PA
Landi
Maria Teresa
MT
D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D015415:Biomarkers; D001822:Body Burden; D003176:Complement C3 / Q000032:analysis; D003181:Complement C4 / Q000032:analysis; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D004268:DNA-Binding Proteins; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000032:analysis; D066298:In Vitro Techniques; D007558:Italy / Q000453:epidemiology; D008214:Lymphocytes / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011153:Population; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis
C497396:ARNT protein, human; D015415:Biomarkers; D003176:Complement C3; D003181:Complement C4; D004268:DNA-Binding Proteins; D004785:Environmental Pollutants; D007136:Immunoglobulins; 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