Metodologie molecolari e genetiche nello studio degli effetti di agenti occupazionali ed ambientali: L'esempio del "seveso molecular epidemiology project"

In 1997, IARC classified 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as carcinogenic to humans, based on sufficient evidence from animal data and limited evidence from human data. A key role in the IARC classification was played by the well-defined mechanism of TCDD action involving the activation of the Arylhydrocarbon Receptor (AhR). Experimental animal and in-vitro studies indicate that AhR levels decrease following TCDD binding. Nearly 20 years after the Seveso accident, we found a decrease in AhR mRNA levels in TCDD-exposed subjects. AhR transcript levels were correlated with plasma TCDD concentrations. Our results may reflect a down-regulation of AhR, similar to that observed in most receptorial systems. We demonstrated, for the first time in humans, that TCDD-related regulation of the AhR pathway, previously observed in experimental studies, may also occur in exposed subjects. Our data are important for extrapolating AhR-mediated effects from experimental models to humans.