title: Evaluation of low doses BPA-induced perturbation of glycemia by toxicogenomics points to a primary role of pancreatic islets and to the mechanism of toxicity.
abstract: Epidemiologic and experimental studies have associated changes of blood glucose homeostasis to Bisphenol A (BPA) exposure. We took a toxicogenomic approach to investigate the mechanisms of low-dose (1 × 10(-9 )M) BPA toxicity in ex vivo cultures of primary murine pancreatic islets and hepatocytes. Twenty-nine inhibited genes were identified in islets and none in exposed hepatocytes. Although their expression was slightly altered, their impaired cellular level, as a whole, resulted in specific phenotypic changes. Damage of mitochondrial function and metabolism, as predicted by bioinformatics analyses, was observed: BPA exposure led to a time-dependent decrease in mitochondrial membrane potential, to an increase of ROS cellular levels and, finally, to an induction of apoptosis, attributable to the bigger Bax/Bcl-2 ratio owing to activation of NF-κB pathway. Our data suggest a multifactorial mechanism for BPA toxicity in pancreatic islets with emphasis to mitochondria dysfunction and NF-κB activation. Finally, we assessed in vitro the viability of BPA-treated islets in stressing condition, as exposure to high glucose, evidencing a reduced ability of the exposed islets to respond to further damages. The result was confirmed in vivo evaluating the reduction of glycemia in hyperglycemic mice transplanted with control and BPA-treated pancreatic islets. The reported findings identify the pancreatic islet as the main target of BPA toxicity in impairing the glycemia. They suggest that the BPA exposure can weaken the response of the pancreatic islets to damages. The last observation could represent a broader concept whose consideration should lead to the development of experimental plans better reproducing the multiple exposure conditions.
authors.affiliation: IRGS, Biogem, Via Camporeale, 83031 Ariano Irpino, Avellino, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Carchia
authors.affiliation: IRGS, Biogem, Via Camporeale, 83031 Ariano Irpino, Avellino, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Porreca
authors.affiliation: STAB VIDA-Investigação e Serviços em Ciências Biológicas, Madan Parque, Caparica, Portugal.
authors.forename: P J
authors.initials: PJ
authors.lastname: Almeida
authors.affiliation: IRGS, Biogem, Via Camporeale, 83031 Ariano Irpino, Avellino, Italy.
authors.forename: F
authors.initials: F
authors.lastname: D'Angelo
authors.affiliation: Department of Science and Technology, University of Sannio, via Port'Arsa 11, Benevento, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Cuomo
authors.affiliation: IRGS, Biogem, Via Camporeale, 83031 Ariano Irpino, Avellino, Italy.|Department of Science and Technology, University of Sannio, via Port'Arsa 11, Benevento, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ceccarelli
authors.affiliation: IEOS-CNR, via Pansini 5, Napoli, Italy.|Molecular Medicine and Medical Biotechnologies, University of Naples 'Federico II', Naples, Italy.
authors.forename: M
authors.initials: M
authors.lastname: De Felice
authors.affiliation: Molecular Medicine and Medical Biotechnologies, University of Naples 'Federico II', Naples, Italy.
authors.forename: M
authors.identifier: http://orcid.org/0000-0002-4001-3856
authors.initials: M
authors.lastname: Mallardo
authors.affiliation: IRGS, Biogem, Via Camporeale, 83031 Ariano Irpino, Avellino, Italy.|Department of Science and Technology, University of Sannio, via Port'Arsa 11, Benevento, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Ambrosino
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D001786:Blood Glucose / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010636:Phenols / Q000633:toxicity*; D043922:Toxicogenetics / Q000379:methods; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds