Acromegaly Is More Severe in Patients With <i>AHR</i> or <i>AIP</i> Gene Variants Living in Highly Polluted Areas

Cannavò, Salvatore; Ragonese, M.; Puglisi, Soraya; Romeo, Placido; Torre, Maria Luisa; Alibrandi, Angela; Scaroni, Carla; Occhi, Gianluca; Ceccato, Filippo; Regazzo, Daniela; Menis, Ernesto De; Sartorato, Paola; Arnaldi, Giorgio; Trementino, Laura; Trimarchi, Francesco; Ferraú, Francesco

doi:10.1210/jc.2015-4191

Cited by 34 publications

(28 citation statements)

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“…From a clinical viewpoint, patients carrying AIP mutations are more often young, male and with large GH- or mixed GH- and prolactin-secreting tumors [48, 53, 54]. Interestingly, the AhR gene itself appears to contribute to severity of acromegaly as polymorphisms and variants in AhR have been associated with more aggressive disease [55, 56]. …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…Acromegaly was observed with increased incidence in a highly polluted industrial region in Italy (Messina, Sicily) (79). The current prevalence of acromegaly is thought to be 330 cases per million inhabitants and the relative risk of developing the disease was estimated to be eight-fold higher in comparison with a non-polluted area in the same province (79,80). In a subsequent study it was found that 9/23 (39%) patients from different highly polluted areas in Italy bore a genetic variant of AHR or AIP, as compared with 25.3% (44/187) of patients from non-polluted regions.…”

Section: Aip Mutations In Fipa and Sporadic Pituitary Adenomasmentioning

confidence: 99%

“…In a subsequent study it was found that 9/23 (39%) patients from different highly polluted areas in Italy bore a genetic variant of AHR or AIP, as compared with 25.3% (44/187) of patients from non-polluted regions. Notably, genetically variant adenomas in polluted areas had a more severe course of acromegaly, characterized by higher IGF-1 values and larger tumor size and worse response to first-line SSAs in comparison with the other groups (80). It is known that AIP forms a complex with AHR, stabilizing it in the cytoplasm together with a dimer of heat-shock proteins 90 and the co-chaperone p23 and AIP protein expression could influence AHR expression (78,81,82).…”

Section: Aip Mutations In Fipa and Sporadic Pituitary Adenomasmentioning

confidence: 99%

Somatic and germline mutations in the pathogenesis of pituitary adenomas

Vandeva

Daly

Pétrossians

et al. 2019

European Journal of Endocrinology

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Pituitary adenomas are frequently occurring neoplasms that produce clinically significant disease in 1:1000 of the general population. The pathogenesis of pituitary tumors is a matter of interest as it could help to improve diagnosis and treatment. Until recently, however, disruptions in relatively few genes were known to predispose to pituitary tumor formation. In the last decade, several more genes and pathways have been described. Germline pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene were found in familial or sporadic pituitary adenomas, usually with an aggressive clinical course. Cyclin-dependent kinase inhibitor 1B (CDKN1B) pathogenic variants lead to multiple endocrine neoplasia type 4 (MEN4) syndrome, in which pituitary adenomas can occur. Xq26.3 duplications involving the gene GPR101 cause X-linked acrogigantism. The pheochomocytoma and/or paraganglioma with pituitary adenoma association (3PAs) syndrome suggests that pathogenic variants in the genes of the succinate dehydrogenase complex or MYC-associated factor X (MAX) might be involved in pituitary tumorigenesis. New recurrent somatic alterations were also discovered in pituitary adenomas, such as, ubiquitin-specific protease 8 (USP8) and USP48 pathogenic variants in corticotropinomas. The aim of the present review is to provide an overview of the genetic pathophysiology of pituitary adenomas and their clinical relevance.

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“…Taking together these results indicate that BZ is an environmental factor that could play an important role in pituitary adenoma responsiveness to SSA therapy. At present, only indirect evidence of the role of benzene exposure in SSA resistance in humans with GH-producing adenomas are available (Cannavò et al 2016). Indeed, in 2016 Cannavò et al observed more frequent SSA resistance in acromegalic patients living in highly polluted areas and carriers of AHR genetic variants.…”

Section: Discussionmentioning

confidence: 99%

“…In the highly polluted area close to Messina (Italy) Cannavò et al (2010) encountered a significantly higher prevalence of acromegaly respect to less polluted areas and to the general population. Patients living in highly polluted areas and carriers of genetic variants affecting normal functioning of the aryl hydrocarbon receptor (AHR) pathway (that is involved in xenobiotics cellular response) present larger pituitary tumors, more severe acromegaly symptoms, and are more frequently SSA resistance (Cannavò et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Benzene affects the response to octreotide treatment of growth hormone secreting pituitary adenoma cells

Zunino

Catalano

Zenga³

et al. 2019

Environmental Research

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Growth hormone (GH) secreting pituitary adenomas are the main cause of acromegaly. Somatostatin analogs are the gold standard of medical therapy; however, resistance represents a big drawback in acromegaly management. We recently demonstrated that benzene (BZ) modifies the aggressiveness of GH-secreting rat pituitary adenoma cells (GH3), increasing GH secretion and altering the synthesis of molecules involved in the somatostatin signaling pathway. Based on these pieces of evidence, this study aimed to evaluate the effects of BZ on octreotide (OCT) efficacy in GH-secreting adenoma cells. In GH3 cells, BZ counteracted the anti-proliferative action of OCT. GH gene expression, unmodified by OCT, remained high in BZ-treated cells as well as after treatment with the association of both. GH secretion, reduced by OCT, was increased after treatment with BZ alone or when the pollutant was used with OCT. The combination of BZ and OCT greatly reduced the gene expression of ZAC1 and SSTR2; and this reduction was also present at a protein level. BZ caused an increase in the protein level of the transcription factor STAT3 and in its phosphorylated form. In the presence of BZ, OCT lost the ability to reduce the phosphorylated protein levels. Finally, in primary cultures of human pituitary adenoma cells, BZ caused an increase in GH secretion. OCT decreased GH secretion, but the addition of BZ reversed the OCT effect. In conclusion, our results suggest that BZ may have an important role in the resistance of pituitary adenomas to the pharmacological treatment with somatostatin analogs.

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Acromegaly Is More Severe in Patients With AHR or AIP Gene Variants Living in Highly Polluted Areas

Abstract: Genetic variants potentially inducing functional abnormalities of the aryl hydrocarbon receptor (AHR) pathway are associated with a more severe acromegaly, increased pituitary tumor size, and somatostatin analog resistance in patients living in HR areas.

Cited by 34 publications

References 30 publications

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

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

Somatic and germline mutations in the pathogenesis of pituitary adenomas

Benzene affects the response to octreotide treatment of growth hormone secreting pituitary adenoma cells

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