Cytochrome P450 1A2 activity and incidence of thyroid disease and cancer after chronic or acute exposure to dioxins.

Abstract

BACKGROUND:

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) is the most toxic congener of a family of structurally and mechanistically related persistent organic pollutants whose effects are mediated through the aryl hydrocarbon receptor (AhR). Induction of CYP1A1/2 by TCDD through the AhR depends on the magnitude and the duration of exposure. We aimed to assess CYP1A2 activity after acute and chronic exposure to TCDD. The Maincy cohort is a sample population from Melun in the Val-de-Seine region in France that lived for at least 5 years close to a waste incinerator emitting polluted vapours (1974-2002) with high concentrations of dioxins (up to 2000 times the maximal recommended values). Acute exposure to TCDD (Viktor Yushchenko) has been described elsewhere by Sorg et al (Toxicol. Sci. 2012; 125:310-317). Both are rare cases of well-identified source of chronic and acute exposure to TCDD.

METHODS:

All subjects underwent a full medical history and physical examination and had a cutaneous examination, and a retro-auricular skin biopsy was taken. A questionnaire was designed and used regarding demographic, personal, environmental and occupational characteristics. CYP1A2 activity was assessed 2 hours after the ingestion of a drink containing caffeine through measurement of the metabolic ratio of paraxanthine (17X) over caffeine (137X) by LC-MS/MS or LC-UV. CYP1A1 expression in skin biopsies was determined by immunohistochemical analysis.

RESULTS:

Forty-seven exposed subjects (age 11-78) and 31 controls were included in the study. Eleven exposed subjects had a history of thyroid disease (23.4%), and 7 (14.8%) had a cancer vs none and 1, respectively, in controls. Nodular skin lesions were found in 13 exposed subjects (27.7%) vs none in controls. Mean CYP1A2 activity of the exposed population was modestly elevated as compared to controls (17X/137X metabolic ratio of 0.475 vs 0.374, P = .051). CYP1A2 was, however, induced (17X/137X, metabolic ratio >0.5) in 27.6% of the exposed cases vs 6.4% of the controls. In contrast, acute dioxin exposure was associated with a strong induction (mean 17X/137X, metabolic ratio of 1.9) still present 29 months after the acute exposure. CYP1A1 was expressed in 59.6% of the skin biopsies (highly expressed in 31.9%) of the Maincy cohort. No correlation between CYP1A2 activity, CYP1A1 expression and clinical manifestations (thyroid disease, cancer, skin lesions) could be demonstrated.

CONCLUSION:

Higher frequencies of dysthyroidism and cancer were detected in the population exposed chronically to dioxins from a waste incinerator. CYP1A2 was induced in 27.6% of the exposed population, while the magnitude of induction was fourfold higher after acute exposure in the case of Yushchenko.

• Authors: Caroline Flora Samer, Yvonne Gloor, Victoria Rollason, Idris Guessous, Fabienne Doffey-Lazeyras, Jean-Hilaire Saurat, Olivier Sorg, Jules Desmeules, Youssef Daali
• Journal: Basic & clinical pharmacology & toxicology (Basic Clin Pharmacol Toxicol) Vol. 126 Issue 3 Pg. 296-303 (Mar 2020) ISSN: 1742-7843 [Electronic] England
• PMID: 31608602 (Publication Type: Journal Article)
• Copyright: © 2019 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Chemical References

• Environmental Pollutants
• Polychlorinated Dibenzodioxins
• CYP1A1 protein, human
• CYP1A2 protein, human
• Cytochrome P-450 CYP1A1
• Cytochrome P-450 CYP1A2

Topics

• Adolescent
• Adult
• Aged
• Child
• Cohort Studies
• Cytochrome P-450 CYP1A1 (metabolism)
• Cytochrome P-450 CYP1A2 (metabolism)
• Environmental Exposure (adverse effects)
• Environmental Pollutants (administration & dosage, toxicity)
• Female
• France (epidemiology)
• Humans
• Incidence
• Male
• Middle Aged
• Neoplasms (epidemiology)
• Polychlorinated Dibenzodioxins (administration & dosage, toxicity)
• Surveys and Questionnaires
• Thyroid Diseases (epidemiology)
• Young Adult