Benzene and 2-ethyl-phthalate induce proliferation in normal rat pituitary cells

Abstract

PurposeEndocrine disruptors are known to modulate a variety of endocrine functions and increase the risk for neoplasia. Epidemiological data reported increased prevalence of pituitary tumors in high industrial areas while genotyping studies showed that mutations in the aryl hydrocarbon receptor (AhR) interacting protein (AIP)—chaperone to the dioxin ligand AhR—gene are linked to predisposition to pituitary tumor development. Aim of the present study was to establish whether endocrine pollutants can induce cell proliferation in normal rat pituitary cells.MethodsPituitary primary cultures were incubated with 250, 650 and 1250 pM benzene or 2-ethyl-phthalate for up to 96 h and viability, energy content and cell proliferation assessed. Expression of pituitary tumor transforming gene (PTTG), cyclin D1 (Ccnd1), AhR and AIP was quantified by RT-qPCR.ResultsIncubation with benzene or 2-ethyl-phthalate increased viability and energy content in pituitary cells. The endocrine disruptors also increased cell proliferation as well as Ccnd1 and PTTG expression. Increased AhR and AIP expression was observed after incubation with the two pollutants.ConclusionsOur findings indicate that benzene and 2-ethyl-phthalate activate AhR/AIP expression and stimulate proliferation in normal rat pituitary cells. This study is the first demonstration that pollutants can induce normal pituitary cells to proliferate and provides a link between epidemiological and genomic findings in pituitary tumors.Electronic supplementary materialThe online version of this article (doi:10.1007/s11102-016-0777-3) contains supplementary material, which is available to authorized users.

Effects of environmental pollutants on signaling pathways in rat pituitary GH3 adenoma cells

“…Finally, none of the tested pollutants affected cell growth or viability. Recently, Tapella et al (2016) reported that 96 hour in vitro treatment with either BZ (250 pM-1.25 nM) or DEHP (250 pM -1.25nM) was able to increase cell viability and proliferation of primary cultures obtained from normal rat pituitary tissue. This different behavior may be explained by different exposure times or the different models used; pollutants could interfere with the growth of normal cells; whereas, the absence of effects on cancerous cells, may be due to an already dysregulated cell cycle.…”

“…The authors therefore hypothesized the involvement of environmental pollutants in the pathogenesis of somatotropinomas. Recently, Tapella et al (2016) demonstrated in vitro that the pollutants BZ and DEHP are able to interfere with normal rat pituitary cell proliferation and to promote gene expression changes at AIP and AHR levels, providing a link between epidemiological and genomic findings in pituitary tumors. However, to date, there are no other studies about the influence of these environmental chemical pollutants on the behavior of pituitary tumors in terms of aggressiveness and potentially drug therapy resistance.…”

Circulating aryl hydrocarbon receptor-interacting protein (AIP) is independent of GH secretion

“…The first recognized partner of AIP is the nuclear receptor AhR, known to bind environmental toxins. The role of the AhR-AIP pathway has been studied in pituitary cells and patients with acromegaly ( 42 , 43 , 44 , 45 , 46 , 47 , 48 ). Several in vitro studies have related exposure to AhR-mediated toxins in GH3 cells to an increase in either proliferation ( 47 ) or GH secretion ( 48 ).…”

“…The role of the AhR-AIP pathway has been studied in pituitary cells and patients with acromegaly ( 42 , 43 , 44 , 45 , 46 , 47 , 48 ). Several in vitro studies have related exposure to AhR-mediated toxins in GH3 cells to an increase in either proliferation ( 47 ) or GH secretion ( 48 ). An epidemiological association was proposed between exposition to environmental pollution and somatotropinoma incidence ( 43 ), although no direct link was found in the area with an inductrial accident involving dioxin ( 42 ).…”

Uncertainty Informed Screening for Safer Solvents used in the Synthesis of Perovskite Based Solar Cells via Machine Learning

“…Aside from the challenge of creating a structured database on solvents from thousands of journal articles, predicting their endocrine disrupting (ED) nature is equally a tough ask. Although the examination of their ED nature is found in some studies [54,55,56,57,58,59,60]…”