Temporal Effects of Bisphenol A on Dopaminergic Neurons: An Experiment on Adult Rats

Ishido, Masami; Masuo, Yoshinori

doi:10.2174/1876325101408010009

Cited by 11 publications

(3 citation statements)

References 33 publications

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“…In line with our findings, Pradyumna and colleagues showed that BPA treatment induced a significant upregulation of both PD-associated αSyn and leucine-rich repeated kinase 2 (LRRK2) proteins in zebrafish 38 . αSyn accumulation in neurons after BPA exposure has also been reported in mammals, being upregulated in the substantia nigra pars compacta of adult rats that were neonatally treated 39 . Moreover, when mice were exposed in utero to human-relevant doses of BPA, αSyn was one of the most upregulated genes as shown by Ingenuity Pathway Analysis 40 .…”

Section: Discussionmentioning

confidence: 63%

Machine learning identifies phenotypic profile alterations of human dopaminergic neurons exposed to bisphenols and perfluoroalkyls

Di Credico,

Weiss,

Corsini

et al. 2023

Sci Rep

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Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by the loss of midbrain dopaminergic neurons. Endocrine disrupting chemicals (EDCs) are active substances that interfere with hormonal signaling. Among EDCs, bisphenols (BPs) and perfluoroalkyls (PFs) are chemicals leached from plastics and other household products, and humans are unavoidably exposed to these xenobiotics. Data from animal studies suggest that EDCs exposure may play a role in PD, but data about the effect of BPs and PFs on human models of the nervous system are lacking. Previous studies demonstrated that machine learning (ML) applied to microscopy data can classify different cell phenotypes based on image features. In this study, the effect of BPs and PFs at different concentrations within the real-life exposure range (0.01, 0.1, 1, and 2 µM) on the phenotypic profile of human stem cell-derived midbrain dopaminergic neurons (mDANs) was analyzed. Cells exposed for 72 h to the xenobiotics were stained with neuronal markers and evaluated using high content microscopy yielding 126 different phenotypic features. Three different ML models (LDA, XGBoost and LightGBM) were trained to classify EDC-treated versus control mDANs. EDC treated mDANs were identified with high accuracies (0.88–0.96). Assessment of the phenotypic feature contribution to the classification showed that EDCs induced a significant increase of alpha-synuclein (αSyn) and tyrosine hydroxylase (TH) staining intensity within the neurons. Moreover, microtubule-associated protein 2 (MAP2) neurite length and branching were significantly diminished in treated neurons. Our study shows that human mDANs are adversely impacted by exposure to EDCs, causing their phenotype to shift and exhibit more characteristics of PD. Importantly, ML-supported high-content imaging can identify concrete but subtle subcellular phenotypic changes that can be easily overlooked by visual inspection alone and that define EDCs effects in mDANs, thus enabling further pathological characterization in the future.

show abstract

Section: Discussionmentioning

confidence: 63%

Machine learning identifies phenotypic profile alterations of human dopaminergic neurons exposed to bisphenols and perfluoroalkyls

Di Credico,

Weiss,

Corsini

et al. 2023

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Accordingly, Pradyumna and colleagues showed that BPA treatment induced a significant upregulation of both PDassociated αSyn and leucine-rich repeated kinase 2 (LRRK2) proteins in zebrafish [33]. αSyn accumulation in neurons after BPA exposure has also been reported in mammals, being upregulated in the substantia nigra pars compacta of adult rats that were neonatally treated [34]. Moreover, when mice were exposed in utero to human-relevant doses of BPA, αSyn was one of the most upregulated genes as shown by Ingenuity Pathway Analysis [35].…”

Section: Discussionmentioning

confidence: 95%

Machine learning identifies phenotypic profile alterations of human dopaminergic neurons exposed to bisphenols and perfluoroalkyls

Di Credico,

Weiss,

Corsini

et al. 2023

Preprint

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Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by the loss of midbrain dopaminergic neurons. Endocrine disruptors (EDs) are active substances that interfere with hormonal signaling. Among EDs, bisphenols (BPs) and perfluoroalkyls (PFs) are chemicals leached from plastics and other household products, and humans are unavoidably exposed to these xenobiotics. Data from animal studies suggest that ED exposure may play a role in PD, but data about the effect of BPs and PFs on human models of the nervous system are lacking. Previous studies demonstrated that machine learning (ML) applied to microscopy data can classify different cell phenotypes based on image features. In this study, the effect of BPs and PFs at different concentrations within the real-life exposure range (0.01, 0.1, 1, and 2 μM) on the phenotypic profile of human stem cell-derived midbrain dopaminergic neurons (mDANs) was analyzed. Cells exposed for 72 hours to the xenobiotics were stained with neuronal markers and evaluated using high content microscopy yielding 126 different phenotypic features. Two different ML models (XGBoost and LightGBM) were trained to classify ED-treated versus control mDANs. ED-treated mDANs were identified with high accuracy (0.92). Assessment of the phenotypic feature contribution to the classification showed that EDs induced a significant increase of alpha-synuclein (αSyn) and tyrosine hydroxylase (TH) staining intensity within the neurons. Moreover, microtubule-associated protein 2 (MAP2) neurite length and branching were significantly diminished in treated neurons. Our study shows that human mDANs are adversely impacted by exposure to EDs, causing their phenotype to shift and exhibit more characteristics of PD. Importantly, ML-supported high-content imaging can identify concrete but subtle subcellular phenotypic changes that can be easily overlooked by visual inspection alone and that define EDs effects in mDANs, thus enabling further pathological characterization in the future.

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“…Several authors sustain that BPA exposure can be associated with neurodevelopmental disorders (autism spectrum disorder, attention de cit hyperactivity disorder) or with neurodegenerative disorders (Parkinson's Disease, amyotrophic lateral sclerosis) (Homberg, 2016;Ishido 2014;Morrice 2018). Although the mechanisms of BPA on brain development are not fully understood, numerous studies sustain that, it may impair neural stem cell proliferation and differentiation, synapse formation and synaptic plasticity, especially in the hippocampus and prefrontal cortex (Ali 2017 ;Carr 2003; Hass 2016).…”

Section: Introductionmentioning

confidence: 99%

Neurotoxicity of Bisphenol A and the Impact of Melatonin Administration on Oxidative Stress, ERK/NF-kB Signaling Pathway, and Behavior in Rats

Sevastre-Berghian

Casandra²,

Gheban³

et al. 2022

Neurotox Res

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Bisphenol A (BPA) exposure can be associated with neurodevelopmental disorders due to impairment of cell proliferation and synaptic development. Our study evaluated the effects of melatonin (MEL) on ambulatory activity, lipid peroxidation, cytokines, ERK/NF-kB signaling pathway in hippocampus and frontal lobe, and histopathological changes in the hippocampus of the BPA-treated rats. The animals were divided in 4 groups: control, BPA, BPA + MEL I, BPA + MEL II. MEL I (20 mg/kg b.w), and MEL II (40 mg/kg b.w.) were orally administered for 28 days. In the 29th day, BPA (1 mg/kg b.w) was intraperitoneally administered and, after 24 h, Open Field Test (OFT) and Elevated Plus Maze (EPM), were conducted. The results showed that MEL II group made signi cantly more entries in the open arms of EPM, travelled signi cantly greater distance and spent more time in the central part of OFT. Malondialdehyde levels were diminished by MEL II in the hippocampus and by MEL I in the frontal lobe. In the hippocampus, MAPK level was signi cantly lowered by both doses of MEL (p < 0.05) while in frontal lobe, only MEL II reduced the MAPK activation. MEL I and II signi cantly decreased the γH2AX and upregulated the NFkB and pNFkB expressions in the hippocampus while MEL II downregulated the MCP1 expression. Both doses of MEL attenuated the BPA-evoked histopathological alterations in the hippocampus. These data indicate that MEL can mediate the neuroprotection against BPA-induced neurotoxicity and improves the behavioral changes suggesting a real potential as protective agent in brain toxicity.Additionally, BPA exposure increases the expression of proin ammatory cytokines such as IL-6, IL-1 b and TNF-a, reduces the expression of anti-in ammatory IL-10, and induces the activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), some other mitogen-activated protein kinase (MAPK) and nuclear factor (NF -kB) pathway (Inadera 2015; Rebolledo-Solleiro 2021).Several in vivo and in vitro models reported that natural compounds (vitamin A, C and E, Quercetin, Lycopene, Gallic acid, Ginseng, Tualang honey) may alleviate BPA -induced -toxicity (Amjad, 2020). Melatonin (MEL), secreted by the pineal gland in the brain, known for its antioxidant and antiapoptotic effects (Lee 2019; Rehman 2019).Considering that oxidative stress appears to be an important contributor to the neurotoxicity induced by BPA, and the antioxidants, with remarkable neuroprotective effects, could play a valuable protective role, our study aimed to evaluate the effects of MEL preadministration on ambulatory activity, lipid peroxidation, in ammatory cytokines, ERK/NF-kB signaling pathway in hippocampus and frontal lobe and histopathological changes in hippocampus of the BPA -treated rats. The BPA was administered in a single dose in rats treated orally with two doses of MEL for 28 days.÷ ersefunctions, suchas, ∘ adianrhythm, e ≠ rgymηbolism and imμ ≠ systemrega --→ r, hasbeenrep or ted → exert ≠ uroprotect has been identi ed as an important factor to neu...

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Temporal Effects of Bisphenol A on Dopaminergic Neurons: An Experiment on Adult Rats

Cited by 11 publications

References 33 publications

Machine learning identifies phenotypic profile alterations of human dopaminergic neurons exposed to bisphenols and perfluoroalkyls

Machine learning identifies phenotypic profile alterations of human dopaminergic neurons exposed to bisphenols and perfluoroalkyls

Machine learning identifies phenotypic profile alterations of human dopaminergic neurons exposed to bisphenols and perfluoroalkyls

Neurotoxicity of Bisphenol A and the Impact of Melatonin Administration on Oxidative Stress, ERK/NF-kB Signaling Pathway, and Behavior in Rats

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