Bisphenol a Induces Autophagy Defects and AIF-Dependent Apoptosis via HO-1 and AMPK to Degenerate N2a Neurons

Lee, Ching-Tien; Hsieh, Ching‐Hua; Wang, Jiz-Yuh

doi:10.3390/ijms222010948

Cited by 9 publications

(7 citation statements)

References 64 publications

(84 reference statements)

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“…Apoptosis can be induced by many kinds of chemicals, and plays a key role in reproductive toxicology 21,22,34–36 . BPA has also shown to induce apoptosis in a variety of cell types 37–40 . In this study, we showed that BPA exposure significantly increased the protein levels of cleaved Caspase‐8, cleaved Caspase‐3 and Bax, as well as decreased the Bcl‐2 protein level, indicating that BPA exposure could induce apoptosis in the testis tissue.…”

Section: Discussionsupporting

confidence: 49%

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Bisphenol A (BPA) induces apoptosis of mouse Leydig cells via oxidative stress

Zhang

Yang

et al. 2022

Environmental Toxicology

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As one of the most frequently produced synthetic compounds worldwide, bisphenol A (BPA) has been widely used in many kinds of products such as appliances, housewares, and beverage cans. BPA has been shown to cause damage to male reproductive system; however, the potential mechanism remains to be investigated. In the present study, BPA exposure decreased the testis and epididymis coefficient, caused a disintegration of germinal epithelium, decreased the density and motility of sperm in the epididymis tissue, and increased the number of abnormal sperm morphology, which indicated that BPA exposure could cause damage to testis. BPA was also shown to induce apoptosis and oxidative stress in the testis tissue. The serum testosterone concentration was decreased in the BPA-treated group, suggesting that BPA could lead to Leydig cell damage. Subsequently, mouse TM3 cell, a kind of mouse Leydig cell line, was utilized to investigate the potential mechanism. Herein, we showed that BPA exposure could inhibit cell viability and induce apoptosis of TM3 cells. Furthermore, oxidative stress in the cells could also be induced by BPA, while the inhibition of oxidative stress by N-acetyl-L-cysteine (NAC), an oxidative stress scavenger, could reverse the inhibition of cell viability and induction of apoptosis by BPA exposure, indicating that oxidative stress was involved in BPA-induced apoptosis of TM3 cells. Finally, RNA-sequencing and real-time PCR were utilized to screen and validate the potential oxidative stress-related genes involving in BPA-induced apoptosis. We found that BPA exposure increased the mRNA levels of oxidative stress-related genes such as Lonp1, Klf4, Rack1, Egln1, Txn2, Msrb1, Atox1, Mtr, and Atp2a2, as well as decreased the mRNA level of Dhfr gene; while NAC could rescue the expression of these genes. Taken together, oxidative stress was involved in BPAinduced apoptosis of mouse Leydig cells.

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Section: Discussionsupporting

confidence: 49%

“…21,22,[34][35][36] BPA has also shown to induce apoptosis in a variety of cell types. [37][38][39][40] In this study, we showed that BPA exposure significantly increased the protein levels of cleaved Caspase-8, cleaved…”

Section: Discussionmentioning

confidence: 53%

Bisphenol A (BPA) induces apoptosis of mouse Leydig cells via oxidative stress

Zhang

Yang

et al. 2022

Environmental Toxicology

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“…The neurotoxicity of this EDC using viability and neuronal differentiation assays was performed, and the results showed that BPA decreased cell viability and axon growth (e.g., by down-regulating MAP2 and GAP43) and that it induced neurotoxicity caused by down-regulation of Bcl-2, initiating apoptosis, causing inhibition of autophagy flux, featured by nuclear translocation of apoptosis-inducing factor (AIF), light chain 3B (LC3B) aggregation, and p62 accumulation. Therefore, the authors confirmed that BPA induces neurotoxicity of neuro2a cells characterized by the (AIF)-dependent apoptosis and p62-related autophagy defects via positive regulation of heme oxygenase-1 (HO-1) and activation of AMP kinase (AMPK) resulting in neuronal degeneration (Lee et al 2021 ). Moreover, in PC12 cells, the mechanism of neuronal apoptosis induced by various BPA concentrations (1, 10, 25, 50, 75, 100, 125, 150 μM) was investigated by the group of Zhang Y.…”

Section: Effects Of Bpa On Animal Modelsmentioning

confidence: 82%

Effect of bisphenol A on the neurological system: a review update

Costa,

Cairrao

2023

Arch Toxicol

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Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) and one of the most produced synthetic compounds worldwide. BPA can be found in epoxy resins and polycarbonate plastics, which are frequently used in food storage and baby bottles. However, BPA can bind mainly to estrogen receptors, interfering with various neurologic functions, its use is a topic of significant concern. Nonetheless, the neurotoxicity of BPA has not been fully understood despite numerous investigations on its disruptive effects. Therefore, this review aims to highlight the most recent studies on the implications of BPA on the neurologic system. Our findings suggest that BPA exposure impairs various structural and molecular brain changes, promoting oxidative stress, changing expression levels of several crucial genes and proteins, destructive effects on neurotransmitters, excitotoxicity and neuroinflammation, damaged blood–brain barrier function, neuronal damage, apoptosis effects, disruption of intracellular Ca2+ homeostasis, increase in reactive oxygen species, promoted apoptosis and intracellular lactate dehydrogenase release, a decrease of axon length, microglial DNA damage, astrogliosis, and significantly reduced myelination. Moreover, BPA exposure increases the risk of developing neurologic diseases, including neurovascular (e.g. stroke) and neurodegenerative (e.g. Alzheimer’s and Parkinson’s) diseases. Furthermore, epidemiological studies showed that the adverse effects of BPA on neurodevelopment in children contributed to the emergence of serious neurological diseases like attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), depression, emotional problems, anxiety, and cognitive disorders. In summary, BPA exposure compromises human health, promoting the development and progression of neurologic disorders. More research is required to fully understand how BPA-induced neurotoxicity affects human health.

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“…BPA is an environmental endocrine disruptor that has been widely studied because of its prevalence in life (Lee et al, 2021). Reliable evidence supports that BPA has the potential to induce male reproductive toxicity in animals and humans.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of VDAC1 prevents oxidative stress and apoptosis induced by bisphenol A in spermatogonia via AMPK/mTOR signaling pathway

Wang

Liu

et al. 2023

J. Toxicol. Sci.

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Bisphenol A (BPA), one of the main components of industrial products, is clinically associated with the increased male infertility rate. However, the underlying molecular mechanism of the BPA-resulted reproductive toxicity is not fully elucidated. Voltage-dependent anion channel 1 (VDAC1) is a pore protein and located at the outer mitochondrial membrane. As a mitochondrial gatekeeper, VDAC1 controls the release of reactive oxygen species (ROS) and the metabolic and energetic functions of mitochondria, and serves as a critical player in mitochondrial-mediated apoptosis. Herein, we explored the role of VDAC1 in BPA-induced apoptosis of spermatogonia. The results showed that BPA increased spermatogonia cell line GC-1 spg cell apoptosis and intracellular ROS level, and suppressed AMPK/mTOR signaling pathway at a dose of 80 μM for 48 hr. Lentivirus-mediated short hairpin RNA targeting VDAC1 (Lv-shVDAC1) silenced VDAC1 expression and enhanced BPA-restricted cell viability. Knockdown of VDAC1 inhibited the apoptosis of BPA-treated GC-1 spg cells determined by with changes of the expressions of pro-apoptotic and anti-apoptotic proteins. Knockdown of VDAC1 also alleviated the BPA-triggered intracellular ROS generation and oxidative stress. Moreover, silence of VDAC1 increased AMPKα1/2 phosphorylation and suppressed mTOR phosphorylation under BPA exposure. Dorsomorphin, an AMPK inhibitor, partially abolished the effects of VDAC1 gene silencing on BPA-stimulated GC-1 spg cells. In conclusion, inhibition of VDAC1 attenuated the BPA-induced oxidative stress and apoptosis and promoted the cell viability in spermatogonia through modulating AMPK/mTOR signaling pathway.

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Bisphenol a Induces Autophagy Defects and AIF-Dependent Apoptosis via HO-1 and AMPK to Degenerate N2a Neurons

Cited by 9 publications

References 64 publications

Bisphenol A (BPA) induces apoptosis of mouse Leydig cells via oxidative stress

Bisphenol A (BPA) induces apoptosis of mouse Leydig cells via oxidative stress

Effect of bisphenol A on the neurological system: a review update

Inhibition of VDAC1 prevents oxidative stress and apoptosis induced by bisphenol A in spermatogonia via AMPK/mTOR signaling pathway

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