Aryl hydrocarbon receptor-interacting protein and pituitary adenomas: A population-based study on subjects exposed to dioxin after the Seveso, Italy, accident

Objective: The pathogenesis of sporadic pituitary tumors is unknown. Loss-of-function mutations of aryl hydrocarbon receptor-interacting protein (AIP) have been identified in patients with familial pituitary tumors. AIP is a chaperone protein with multifunction properties, including modulation of the transcriptional activity of the aryl hydrocarbon receptor, which mediates toxicological and carcinogenic dioxin effects. Design: We investigated the incidence of pituitary tumors in the Seveso population exposed to 2,3,7,8- tetrachlorodibenzo-para-dioxin following an industrial accident in 1976. Methods: Through the hospital discharge registration system of Lombardy Region, we identified incident cases of pituitary adenomas between 1976 and 1996 in the Seveso population, subdivided in zone A (n=804), B (n=5.941), and R (n=38.624) according to high, intermediate, and low exposure to dioxin respectively, and in the surrounding non-contaminated area, as reference (n=232745). Results: We identified 42 pituitary adenomas in the reference area, I prolactinoma in zone A (rate ratio (RR) 6.2; 95% CI 0.9-45.5, P=0.07), 2 nonfuctioning pituitary tumors (NFPAs) in zone B (RR 1.9; 95% CI 0.5-7.7, P=0.39), and 3 prolactinomas and 2 NFPAs in zone R (RR 0.7; 95% CI 0.3-1.8, P= 0.48). Conclusions: The study is unique with regard to the availability of epidemiological and clinical data in an area of relatively pure dioxin exposure. The study indicates no statistically significant increase of incident pituitary tumors in this area, although the tendency toward a higher risk (three cases in zones A and B) of pituitary tumors in subjects exposed to high-intermediate dioxin concentrations in comparison with nonexposed population suggests the need for extended follow-up.