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

Several studies associate foetal human exposure to bisphenol A (BPA) to metabolic/endocrine diseases, mainly diabesity. They describe the role of BPA in the disruption of pancreatic beta cell, adipocyte and hepatocyte functions. Indeed, the complexity of the diabesity phenotype is due to the involvement of different endoderm-derived organs, all targets of BPA. Here, we analyse this point delineating a picture of different mechanisms of BPA toxicity in endoderm-derived organs leading to diabesity. Moving from epidemiological data, we summarize the in vivo experimental data of the BPA effects on endoderm-derived organs (thyroid, pancreas, liver, gut, prostate and lung) after prenatal exposure. Mainly, we gather molecular data evidencing harmful effects at low-dose exposure, pointing to the risk to human health. Although the fragmentation of molecular data does not allow a clear conclusion to be drawn, the present work indicates that the developmental exposure to BPA represents a risk for endoderm-derived organs development as it deregulates the gene expression from the earliest developmental stages. A more systematic analysis of BPA impact on the transcriptomes of endoderm-derived organs is still missing. Here, we suggest in vitro toxicogenomics approaches as a tool for the identification of common mechanisms of BPA toxicity leading to the diabesity in organs having the same developmental origin.

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.

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.

Enhanced sensitivity to group II mGlu receptor activation at corticostriatal synapses in mice lacking the familial parkinsonism-linked genes PINK1 or Parkin.

An altered glutamatergic input at corticostriatal synapses has been shown in experimental models of Parkinson's disease (PD). In the present work, we analyzed the membrane and synaptic responses of striatal neurons to metabotropic glutamate (mGlu) receptor activation in two different mouse models of inherited PD, linked to mutations in PINK1 or Parkin genes. Both in PINK1 and Parkin knockout ((-/-)) mice, activation of group I mGlu receptors by 3,5-DHPG caused a membrane depolarization coupled to an increase in firing frequency in striatal cholinergic interneurons that was comparable to the response observed in the respective wild-type (WT) interneurons. The sensitivity to group II and III mGlu receptors was tested on cortically-evoked excitatory postsynaptic potentials (EPSPs) recorded from medium spiny neurons (MSNs). Both LY379268 and L-AP4, agonists for group II and III, respectively, had no effect on intrinsic membrane properties, but dose-dependently reduced the amplitude of corticostriatal EPSPs. However, both in PINK1(-/-) and Parkin(-/-) mice, LY379268, but not L-AP4, exhibited a greater potency as compared to WT in depressing EPSP amplitude. Accordingly, the dose-response curve for the response to LY379268 in both knockout mice was shifted leftward. Moreover, consistent with a presynaptic site of action, both LY379268 and L-AP4 increased the paired-pulse ratio either in PINK1(-/-) and Parkin(-/-) or in WT mice. Acute pretreatment with L-dopa did not rescue the enhanced sensitivity to LY379268. Together, these results suggest that the selective increase in sensitivity of striatal group II mGlu receptors represents an adaptive change in mice in which an altered dopamine metabolism has been documented.

Striatal metabotropic glutamate receptors as a target for pharmacotherapy in Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopamine (DA)-containing neurons in the substantia nigra pars compacta (SNc). The symptoms are resting tremor, slowness of movement, rigidity and postural instability. Evidence that an imbalance between dopaminergic and cholinergic transmission takes place within the striatum led to the utilization of DA precursors, DA receptor agonists and anticholinergic drugs in the symptomatic therapy of PD. However, upon disease progression the therapy becomes less effective and debilitating effects such as dyskinesias and motor fluctuations appear. Hence, the need for the development of alternative therapeutic strategies has emerged. Several observations in different experimental models of PD suggest that blockade of excitatory amino acid transmission exerts antiparkinsonian effects. In particular, recent studies have focused on metabotropic glutamate receptors (mGluRs). Drugs acting on group I and II mGluRs have indeed been proven useful in ameliorating the parkinsonian symptoms in animal models of PD and therefore might represent promising therapeutic targets. This beneficial effect could be due to the reduction of both glutamatergic and cholinergic transmission. A novel target for drugs acting on mGluRs in PD therapy might be represented by striatal cholinergic interneurons. Indeed, the activation of mGluR2, highly expressed on this cell type, is able to reduce calcium-dependent plateau potentials by interfering with somato-dendritic N-type calcium channel activity, in turn reducing ACh release in the striatum. Similarly, the blockade of both group I mGluR subtypes reduces cholinergic interneuron excitability, and decreases striatal ACh release. Thus, targeting mGluRs located onto cholinergic interneurons might result in a beneficial pharmacological effect in the parkinsonian state.

Mitochondrial toxins in Basal Ganglia disorders: from animal models to therapeutic strategies.

Current knowledge of the pathogenesis of basal ganglia disorders, such as Huntington's disease (HD) and Parkinson's disease (PD) appoints a central role to a dysfunction in mitochondrial metabolism. The development of animal models, based upon the use of mitochondrial toxins has been successfully introduced to reproduce human disease, leading to important acquisitions. Most notably, experimental evidence supports the existence, within basal ganglia, of a peculiar regional vulnerability to distinct mitochondrial toxins. MPTP and rotenone, both selective inhibitors of mitochondrial complex I have been extensively used to mimic PD. Accordingly, in human PD, a specific dysfunction of complex I activity was found in vulnerable dopaminergic neurons of the substantia nigra. Conversely, in HD a selective impairment of mitochondrial succinate dehydrogenase, key enzyme in complex II activity was found in medium spiny neurons of the caudate-putamen. The relevance of such finding is further demonstrated by the evidence that toxins able to primarily target mitochondrial complex II, such as malonic acid and 3-nitropropionic acid (3-NP), strikingly reproduce the main phenotypic and pathological features of HD.Despite the advances obtained from these experimental models, a deeper understanding of the molecular and cellular mechanisms underlying such neuronal vulnerability is lacking.The present review provides a brief survey of currently utilized animal models of mitochondrial intoxication, in attempt to address the cellular mechanisms triggered by energy metabolism failure and to identify potential therapeutic targets.

Modulatory action of metabotropic glutamate receptor (mGluR) 5 on mGluR1 function in striatal cholinergic interneurons.

Within basal ganglia, group I metabotropic glutamate receptor subtypes (mGluR1 and 5) frequently co-localize in the same neuron. However, little is known about how these receptors functionally interact. We addressed this issue by means of electrophysiological recordings of striatal cholinergic interneurons, a neuronal subtype that co-express both group I mGluRs. The group I non-selective agonist 3,5-DHPG induced a membrane depolarization/inward current that was prevented by co-application of LY 367385, a selective mGluR1 antagonist, and SIB 1757 or MPEP, blockers of mGluR5 subtype. The reversal potential for the response to 3,5-DHPG was close to the equilibrium potential for potassium channels. Repeated bath or focal applications of 3,5-DHPG induced a progressive decline in the amplitude of the membrane depolarization, suggesting that group I mGluRs undergo receptor desensitization. Interestingly, in the presence of the mGluR5 blocker, SIB 1757, this event was not observed, whereas it occurred in LY 367385. PKC blockers chelerythrine and calphostin C mimicked the inhibitory effect of SIB 1757. In a subset of interneurons, in MPEP or SIB 1757, 3,5-DHPG induced a 0.5-1 Hz oscillatory response, that was prevented by L-type Ca2+ channel blockers, and by the tyrosine kinase inhibitors genistein and lavendustin. Together, these data suggest that mGluR5 modulates mGluR1 activity to shape cell excitability.