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.

Neurochemical characterization of the enteric neurons within the porcine jejunum in physiological conditions and under the influence of bisphenol A (BPA)

“…It should be noted that the toxic effects of LDs of this substance are not fully explained. The previous studies conducted on experimental animals do not provide a clear answer of what daily dose of BPA is completely safe for the living organism, because the lowest levels of this substance at which the symptoms of the intoxication were noted, clearly depend on animal species, internal organ studied, and routes of toxin administration . Therefore, the determination of tolerable daily intake (TDI) for BPA encounters difficulties.…”

“…It has been reported that exposure to this toxin affects the endocrine and immune systems, contributing to various metabolic disorders and diseases, such as obesity and diabetes . Moreover, it is known that BPA affects the liver, pancreas, and kidneys . Previous studies have shown that this toxin causes changes in the heart and blood vessels, which may lead to hypertension, heart attack, atherosclerosis, and stroke …”

“…16 Moreover, it is known that BPA affects the liver, pancreas, and kidneys. [17][18][19] Previous studies have shown that this toxin causes changes in the heart and blood vessels, which may lead to hypertension, heart attack, atherosclerosis, and stroke. 20,21 Despite numerous studies on the influence of BPA on the living organisms, several aspects of the toxic properties of this substance remain unexplained, including the impact of this substance on the enteric nervous system (ENS).…”

Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo

“…Moving from our experience143233, we planned an in vitro toxicogenomics experiment, in differentiated cells (immortalized thyrocytes), to identify gene signatures, mechanisms of toxicity or/and adverse outcomes potentially active in vivo of two pesticides, ETU and CPF. They were chosen for their known effects on thyroid physiology1011, up to now not characterized at the level of thyroid gene expression.…”

Molecular targets of developmental exposure to bisphenol A in diabesity: a focus on endoderm‐derived organs

“…and of Bax (induced) and Bcl2 (reduced) gene expression in beta cells failure upon exposure . Similar results were shown in ex vivo mouse and rat pancreatic islets .…”