Polystyrene nanoparticles trigger aberrant condensation of TDP-43 and amyotrophic lateral sclerosis-like symptoms.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the dysfunction and progressive death of cerebral and spinal motor neurons. Preliminary epidemiological research has hinted at a relationship between environmental risks and the escalation of ALS, but the underlying reasons remain mostly mysterious. Here we show that nanosize polystyrene plastics (PS) induce ALS-like symptoms and illustrate the related molecular mechanism. When exposed to PS, cells endure internal oxidative stress, which leads to the aggregation of TAR DNA-binding protein 43 kDa (TDP-43), triggering ALS-like characteristics. In addition, the oxidized heat shock protein 70 fails to escort TDP-43 back to the nucleus. The cytoplasmic accumulation of TDP-43 facilitates the formation of a complex between PS and TDP-43, enhancing the condensation and solidification of TDP-43. These findings are corroborated through in silico and in vivo assays. Altogether, our work illustrates a unique toxicological mechanism induced by nanoparticles and provides insights into the connection between environmental pollution and neurodegenerative disorders.

Long-term polystyrene nanoplastic exposure disrupt hepatic lipid metabolism and cause atherosclerosis in ApoE-/- mice.

Nanoplastics (NPs) exposure is usually linked with abnormal inflammation and oxidative stress, which are high-risk triggers of atherosclerosis; however, whether this exposure causes the development of atherosclerosis is vague. Here, we found that PS NPs co-exposure with ox-LDL induces significant accumulation of lipid, as well as oxidative stress and inflammation in RAW264.7 macrophages. Using an ultrasound biomicroscope (UBM), we observed the emergence of atherosclerotic plaques at the aortic arch of apolipoprotein knockout (ApoE-/-) mice after being exposed to PS NPs for three months. Oil-red O and hematoxylin-eosin (H&E) staining at the mice's aortic root also observed the deposition of lipids with plaque formation. Moreover, the development of atherosclerotic disease is associated with disturbances in lipid metabolism and oxidative stress damage in the mice liver. In conclusion, this study provides additional evidence to further understand the possible cardiovascular damage caused by NPs exposure.

Oral exposure of polystyrene microplastics and doxycycline affects mice neurological function via gut microbiota disruption: The orchestrating role of fecal microbiota transplantation.

The debris of plastics with a size < 5 mm, called microplastics, possess long-lived legacies of plastic pollution and a growing threat to human beings. The adverse effects and corresponding molecular mechanisms of microplastics are still largely unknown and must be prioritized. Antibiotics commonly co-existed with microplastics; the current study investigated the syngenetic toxic effect of doxycycline (Dox) and polystyrene microplastics (PS). Specifically, we found that Dox combined with PS exposure perturbed gut microbiota homeostasis in mice, which mediated brain lesions and inflammation with a concomitant decline in learning and memory behaviors through the gut-brain axis. Of note, PS exposure resulted in intestinal damage and structural change, but Dox did not accelerate the disruption of intestinal barrier integrity in PS-treated mice. Interestingly, fecal microbiota transplantation (FMT) can reverse neurological impairment caused by combined PS and Dox exposure via compensating gut microbes; therefore, the learning and memory abilities of mice were also recovered. This work not only provides insights into the syngenetic effect of microplastics and antibiotics and highlights their distal neurotoxicity through the gut-brain axis but also offers a promising strategy against their combined toxicity.

Exosome Heterogeneity Affects the Distal "Barrier-Crossing" Trafficking of Exosome Encapsulated Quantum Dots.

The biological activities of nanoparticles (NPs), which include endocytosis by macrophages and subsequent intracellular degradation and/or release, transfer to other cells, or translocation across tissue barriers, highly depend on their fate in living organisms. Yet, translocation across barriers, especially the distal "barrier-crossing" trafficking of NPs, is still unclear. The exosome (Exo) plays a crucial role in intercellular communication and biological barrier trafficking. Here, we report that ZnCdSe@ZnS quantum dots (QDs), as a representation of NPs in biomedical applications, could cross the blood-brain barrier and approach the mouse brain via active Exo encapsulation. By employing multiple techniques, we demonstrated that QDs were internalized by macrophages (J774A.1) and tumor cells (HeLa) and then released to the extracellular environment along with Exo. Exo encapsulation facilitates the distal barrier-crossing trafficking of QDs in vivo, while Exo biogenesis inhibitor GW4869 suppressed the QDs enriched in the brains of mice with a 4T1-Luc breast cancer xenograft. Interestingly, Exo heterogeneity affects the distal trafficking of enveloped QDs. Exo derived from tumorous HeLa cells, not macrophages, that were enriched in functional proteins with cell adhesion, cell migration, axon guidance, and cell motility, showed a better capacity for the remote trafficking of QDs. This study proposes Exo as a vehicle to deliver exogenous NPs to translocate across the distal barrier and provides further information for biomedical application and the risk assessment of NPs.

Coronal ApoE Protein Combines with LRP1 to Inactivate GSK3ß That Mitigates Silica Nanoparticle-Induced Brain Lesion.

Silica nanoparticles (SiO2 NPs) are widely used engineered materials that warrant their obvious environmental exposure risk. Our previous study has shown that different routes of SiO2 NP exposure on the glycogen synthase kinase 3 beta (GSK3ß) activity were related to the serum proteins enriched on the surface of SiO2 NPs, which implied that a particular protein in the serum changed the inherent toxic behavior of SiO2 NPs and inhibited the activation of GSK3ß by SiO2 NPs. Here, we identified that the SiO2 NP surface enriched a large amount of apolipoprotein E (ApoE), and the ApoE protein corona bound to the lipoprotein receptor-related protein 1 (LRP1) to inactivate GSK3ß, thereby reducing the damage of SiO2 NPs to the brain. This work presented the first evidence that specific biocorona reduced the toxicity of SiO2 NPs at the molecular level, which helped to elucidate the role of specific corona components on nanotoxicity.

Environmentally Relevant Concentrations of Microplastic Exposure Cause Cholestasis and Bile Acid Metabolism Dysregulation through a Gut-Liver Loop in Mice.

The massive production of plastics causes the ubiquitous existence of microplastics (MPs) in the biota, therefore, posing exposure risks and potential health concerns to human beings. However, the exact mechanisms of MPs-induced toxicities and abnormalities are largely unknown. In this study, we developed a mouse model of gavage polystyrene microplastics (PS MPs) for 30 days. We found that PS MPs can damage the intestinal barrier, accumulate in the liver tissue, and cause injury. The liver and intestine are both highly associated with bile acid (BA) metabolism. Indeed, we found that PS MPs dysregulate BA synthesis and efflux-related gene expression in the liver, causing cholestasis. Tandemly, PS MPs alter the ratio of primary to secondary BA in the feces by affecting the composition of the intestinal flora. At last, PS MPs alter mice's fecal BA profile, which affects normal BA metabolism. Taken together, the present study provides robust data on the mechanism of toxicity of MPs causing the disturbance of BA metabolism via a 4-step gut-liver loop.

Silica Nanoparticle Exposure Implicates ß-Amyloid (1-42) Inbound and the Accelerating Alzheimer's Disease Progression in Mice Overexpressing Mutated Forms of Human Amyloid Precursor Protein and Presenilin 1 Genes.

The increasing nanoparticle (NP) applications in the biomedical field have become an emerging concern regarding human health. NP exposure may play a role in the accelerating Alzheimer's disease (AD) progression; however, the etiology of this disorder is complex and remains largely unclear. Here, we identified that intravenous injection of silica NPs (SiNPs) caused the blood-brain barrier breakdown via downregulating tight junction-related gene expressions. Meanwhile, SiNPs upregulate the transport receptor for advanced glycation end products (RAGE) that govern the ß-amyloid (Aß) influx to the brain; however, low-density lipoprotein receptor-related protein 1 (LRP1) that controls the efflux of Aß from the brain was not affected. Consequently, an increase in Aß burden in the brain of SiNP-challenged APP/PS1 mice was found. Intriguingly, plasma apolipoprotein E (ApoE) adsorbed on the surface of SiNPs partially relieves this effect. Using ApoE knockout (ApoE-/-) mice, we confirmed that SiNPs covered with serum without ApoE showed further elevated AD symptoms. Together, this study offered a compilation of data to support the potential risk factors of NP exposure and AD pathology.

Long-term pulmonary iron oxide nanoparticles exposure disrupts hepatic iron-lipid homeostasis and increases plaque vulnerability in ApoE-/- mice.

Iron oxide nanoparticles (Fe3O4 NPs) have attracted great attention due to their extensive applications, which warranted their environmental concerns. Although recent advances have proposed the relevance of Fe3O4 NPs to cardiovascular disease, the intrinsic mechanisms underlying the effects of NPs remain indistinct. ApoE-/- mice were chosen as a long-term exposure model to explore the immanent association between respiratory exposure to Fe3O4 NPs and the development of cardiovascular diseases. Pulmonary exposure to 20 nm and 200 nm Fe3O4 NPS resulted in significant lung injury, and pulmonary histopathological examination displayed inflammatory cell infiltration, septal thickening and alveolar congestion. Intriguingly, liver iron deposition and variations in the hepatic lipid homeostasis were found in Fe3O4 NPs-exposed mice, eventually leading to dyslipidemia, hinting the potential cardiovascular toxicity of Fe3O4 NPs. In addition, we not only found that Fe3O4 NPs exposure increased aortic plaque area, but also increased M1 macrophages in the plaque, which yielding plaque vulnerability in ApoE-/- mice Of note, 20 nm Fe3O4 NPs showed enhanced capability on the progression of atherosclerosis than 200 nm Fe3O4 NPs. This study may propose the potential mechanism for adverse cardiovascular disease induced by Fe3O4 NPs and provide convincing evidence for the safety evaluation of Fe3O4 NPs.

The redox activity of polychlorinated biphenyl quinone metabolite orchestrates its pro-atherosclerosis effect via CAV1 phosphorylation.

Further investigations are required to prove that polychlorinated biphenyls (PCBs) exposure is a cardiovascular disease risk factor. Unlike previous studies that attributed the atherogenic effect of PCBs to aryl hydrocarbon receptor activation, we illustrated a new mechanism involved in the redox reactivity of PCBs. We discover the redox reactivity of quinone moiety is the primary factor for PCB29-pQ-induced proinflammatory response, which highly depends on the status of caveolin 1 (CAV1) phosphorylation. PCB29-pQ-mediated CAV1 phosphorylation disrupts endothelial nitric oxide synthase, toll-like receptor 4, and reduces interleukin-1 receptor-associated kinase 1 binding with CAV1. Phosphorylated proteomics analysis indicated that PCB29-pQ treatment significantly enriched phosphorylated peptides in protein binding functions, inflammation, and apoptosis signaling. Meanwhile, apolipoprotein E knockout (ApoE-/-) mice exposed to PCB29-pQ had increased atherosclerotic plaques compared to the vehicle group, while this effect was significantly reduced in ApoE-/-/CAV1-/- double knockout mice. Thus, we hypothesis CAV1 is a platform for proinflammatory cascades induced by PCB29-pQ on atherosclerotic processes. Together, these findings confirm that the redox activity of PCB metabolite plays a role in the etiology of atherosclerosis.

Long-term exposure of molybdenum disulfide nanosheets leads to hepatic lipid accumulation and atherogenesis in apolipoprotein E deficient mice.

Before their large-scale applications, it is necessary to understand the biological effects of nanomaterials. Although two-dimensional nanomaterials (2D NMs) molybdenum disulfide nanosheets (MoS2 NSs) are promising in biomedical fields, the current knowledge regarding their toxicities is inadequate. Using apolipoprotein E deficient (ApoE-/-) mice as a long-term exposure model, this study demonstrated that intravenous (i.v.) injection of MoS2 NSs most accumulated in the liver and caused in situ hepatic damage. Histopathological examination indicated severe infiltration of inflammatory cells and irregular central veins in the MoS2 NSs-treated mouse liver. Meanwhile, the overwhelming expressions of inflammatory cytokines, dyslipidemia, and dysregulated hepatic lipid metabolism implied the potential vascular toxicity of MoS2 NSs. Indeed, our result supported that MoS2 NSs exposure is highly associated with atherosclerotic progression. This study provided the first line of evidence on the vascular toxicity of MoS2 NSs, which remind scientists to pay attention to the rational use of MoS2 NSs, especially in the biomedical fields.

Polybrominated diphenyl ether quinone exposure leads to ROS-driven lysosomal damage, mitochondrial dysfunction and NLRP3 inflammasome activation.

Polybrominated diphenyl ethers (PBDEs) are aromatic compounds that containing bromine atoms, which possess high efficiency, good thermal stability. However, PBDEs had various known toxic effects and were characterized as persistent environmental pollutants. Exposure to a quinone-type metabolite of PBDEs (PBDEQ) is linked with excess production of intracellular reactive oxygen species (ROS) in our previous studies. Here, we observed that PBDEQ exposure led to ROS and mitochondrial dysfunction, which promoted canonical and non-canonical Nod-like receptor protein 3 (NLRP3) inflammasome activation. Further experiments demonstrated that PBDEQ exposure activated Toll-like receptors (TLRs), subsequently regulating nuclear factor kappa B (NF-κB) signaling. Moreover, lysosomal damage and K+ efflux were involved in PBDEQ-driven NLRP3 inflammasome activation. Our in vivo study also illustrated that PBDEQ administration induced liver inflammation in male C57BL/6J mice. Cumulatively, our current finding provided novel insights into PBDEQ-induced pro-inflammatory responses.

Eryptosis is an indicator of hematotoxicity in the risk assessment of environmental amorphous silica nanoparticles exposure: The role of macromolecule corona.

Silica nanoparticles (SiO2 NPs) have been widely manufactured for various applications and unintentionally generated in various industrial processes. SiO2 NPs exposure is potentially hazardous to human health. Incremental evidence has indicated the presence of SiO2 NPs in systemic circulation, which warranted their interaction with blood components. Due to the obvious weakness of hemolysis in the risk assessment of environmental NPs, we for the first time use eryptosis as a sensitive indicator to assess the hematotoxicity of SiO2 NPs. In vitro results showed that the exposure of erythrocytes to pristine SiO2 NPs resulted in typical features of eryptosis, including oxidative stress, calcium influx, phosphatidylserine externalization and hemolysis. However, SiO2 NPs covered with mouse plasma (SiO2@MP) or grafted with polyvinylpyrrolidone (SiO2@PVP) did not stimulate eryptosis. Interestingly, neither bare nor macromolecule-decolorated SiO2 NPs caused eryptosis in our in vivo mouse model, highlighting the protective role of coronal proteins on the amelioration of SiO2 NPs-induced hematotoxicity. These results emphasized the influences of surface modification on the toxicity of environmental NPs.

Evaluation of Early Biomarkers of Atherosclerosis Associated with Polychlorinated Biphenyl Exposure: An in Vitro and in Vivo Study.

BACKGROUND: Miscellaneous cardiovascular risk factors have been defined, but the contribution of environmental pollutants exposure on cardiovascular disease (CVD) remains underappreciated. OBJECTIVE: We investigated the potential impact of typical environmental pollutant exposure on atherogenesis and its underlying mechanisms. METHODS: We used human umbilical vein endothelial cells (HUVECs) and apolipoprotein E knockout (ApoE-/-) mice to investigate how 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ, a toxic polychlorinated biphenyl metabolite) affects atherogenesis and identified early biomarkers of CVD associated with PCB29-pQ exposures. Then, we used long noncoding RNAs (lncRNAs) HDAC7-AS1-overexpressing ApoE-/- mice and apolipoprotein E/caveolin 1 double-knockout (ApoE-/-/CAV1-/-) mice to address the role of these early biomarkers in PCB29-pQ-induced atherogenesis. Plasma samples from patients with coronary heart disease (CHD) were also used to confirm our findings. RESULTS: Our data indicate that lncRNA HDAC7-AS1 bound to MIR-7-5p via argonaute 2 in PCB29-pQ-challenged HUVECs. Our mRNA sequencing assay identified transforming growth factor-ß2 (TGF-ß2) as a possible target gene of MIR-7-5p; HDAC7-AS1 sponged MIR-7-5p and inhibited the binding of TGF-ß2 to MIR-7-5p. The effect of PCB29-pQ-induced endothelial injury, vascular inflammation, development of plaques, and atherogenesis in ApoE-/- mice was greater with MIR-7-5p-mediated TGF-ß2 inhibition, whereas HDAC7-AS1-overexpressing ApoE-/- mice and ApoE-/-/CAV1-/- mice showed the opposite effect. Consistently, plasma levels of HDAC7-AS1 and MIR-7-5p were found to be significantly associated individuals diagnosed with CHD. DISCUSSIONS: These findings demonstrated that a mechanism-based, integrated-omics approach enabled the identification of potentially clinically relevant diagnostic indicators and therapeutic targets of CHD mediated by environmental contaminants using in vitro and in vivo models of HUVECs and ApoE-/- and ApoE-/-/CAV1-/- mice. https://doi.org/10.1289/EHP9833.

Polychlorinated biphenyl quinone exposure promotes breast cancer aerobic glycolysis: An in vitro and in vivo examination.

Polychlorinated biphenyls (PCBs) were classified as group I carcinogenic to humans, as their toxicological mechanisms have been associated with cancer initiation and promotion. However, whether PCBs have effects on cancer progression are still largely veiled. Here, we for the first time discovered that a PCB quinone-type metabolite, namely PCB29-pQ, exposure significantly promoted aerobic glycolysis, a hallmark property of metabolic reprogramming in cancer progression. PCB29-pQ exposure activated corresponding glucose transporter type 1 (GLUT1)/integrin ß1/Src/focal adhesion kinase (FAK) signaling pathway in breast cancer MDA-MB-231 cells. Conversely, the inhibition of GLUT1 reversed this effect, as well as the ability of migration and invasion of MDA-MB-231 cells. In addition, PCB29-pQ-induced breast cancer metastasis in 4T1-luc cell inoculated nude mice is repressed by GLUT1 inhibition. Overall, our results demonstrated a novel mechanism that PCB29-pQ exposure promotes aerobic glycolysis in both in vitro and in vivo breast cancer models in a GLUT1-dependent fashion, which may provide a strategy to prevent breast cancer cell spread.

Polybrominated Diphenyl Ether Quinone Exposure Induces Atherosclerosis Progression via CD36-Mediated Lipid Accumulation, NLRP3 Inflammasome Activation, and Pyroptosis.

Polybrominated diphenyl ethers (PBDEs) are used worldwide in brominated flame retardants. Although due to the forbiddance of their application, PBDEs continuously exist in the environment due to their persistence. Therefore, it is important to expand the understanding of their potential toxicities and human risks. The underlying cardiovascular toxicological mechanisms of PBDEs are still largely unknown. Our previous studies indicated that PBDE quinone-type metabolite (PBDEQ) exposure causes reactive oxygen species (ROS)-driven cytotoxicity and various types of programmed cell death. Here, we first reported PBDEQ exposure induces atherosclerosis progression in bone marrow-derived macrophages (BMDMs) isolated from wild-type C57BL/6 or CD36-/- mice and J774A.1 macrophage models. First, we found that PBDEQ exposure induced lipid accumulation in oxidized low-density lipid (Ox-LDL)-treated J774A.1 macrophages. Consistently, in J774A.1 macrophages, PBDEQ exposure resulted in NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and pyroptosis. CD36, a scavenger receptor responsible for the mediation of Ox-LDL uptake, was upregulated upon PBDEQ treatment. On the contrary, genetic knockout of CD36 or CD36 silencing by small interfering RNA efficiently attenuates PBDEQ-promoted lipid accumulation in BMDMs and J774A.1 macrophages. These findings highlight the effect of CD36 on the cardiovascular toxicity of PBDEs, which provides a better understanding of the pro-atherosclerosis effect of PBDEs.

Polybrominated diphenyl ethers quinone-induced intracellular protein oxidative damage triggers ubiquitin-proteasome and autophagy-lysosomal system activation in LO2 cells.

Polybrominated diphenyl ethers (PBDEs), a kind of flame retardants, were widely used in the furniture, textile and electronics industries. Because of their lipophilic, persistent and bio-accumulative properties, PBDEs were listed on the Stockholm Convention as typical persistent organic pollutants (POPs). We have previously reported that a highly active, quinone-type metabolite of PBDEs (PBDEQ) causes DNA damage and subsequently triggers apoptosis. However, it is remaining unclear whether PBDEQ provokes protein damage and stimulates corresponding signaling cascade. Using human normal liver (LO2) cells as an in vitro model, we demonstrated that PBDEQ causes oxidative protein damage through excess reactive oxygen species (ROS). Consistently, we found PBDEQ exposure causes the depletion of protein thiol group, the appearance of carbonyl group and the accumulation of protein aggregates. Endoplasmic reticulum (ER) stress was involved in the repair of oxidized proteins. Under the scenario of severe damage, LO2 cells degrade oxidized proteins through ubiquitin-proteasome system (UPS) and autophagy. The blockage of these protein degradation pathways aggravates PBDEQ-induced cytotoxicity in LO2 cells, whilst antioxidant N-acetyl-cysteine (NAC) rescues PBDEQ-induced oxidative protein damage conversely. In summary, our current study first demonstrated PBDEQ-induced protein oxidative damage in LO2 cells, which offer a better understanding of the cytotoxicity of PBDEs and corresponding metabolites.

Tetrachlorobenzoquinone exposure triggers ferroptosis contributing to its neurotoxicity.

Halogenated quinones are representative metabolites of persistent organic pollutants. Tetrachlorobenzoquinone (TCBQ) is a reactive metabolite of the widely used fungicide hexachlorobenzene (HCB) and wood preservative pentachlorophenol (PCP). Our previous studies have demonstrated that TCBQ induced neuron-like cell apoptosis in a reactive oxygen species (ROS)-dependent manner. Here, we found that TCBQ caused lipid peroxidation and cellular morphological changes including shrinked mitochondrial size, suggesting the involvement of a recently uncovered form of programmed cell death (PCD), ferroptosis. Indeed, we then identified that ferroptosis is a novel PCD driven by TCBQ, which was correlated with a decrease in glutathione peroxidase 4 (GPX4) level and iron accumulation by altering iron metabolism. Notably, nuclear factor erythroid-derived 2-like 2 (Nrf2) is a negative regulator in modulating the outcomes of ferroptosis as an adaptive cellular defense response. Nrf2 activation enhanced iron storage capacity and GPX4 activity by elevating ferritin heavy chain 1 (FTH1) expression and glutathione (GSH) level, respectively. On the contrary, Nfe2l2 (Nrf2) deficiency enhanced PC12 cells susceptibility to ferroptosis.

Polychlorinated biphenyl quinone induced the acquisition of cancer stem cells properties and epithelial-mesenchymal transition through Wnt/ß-catenin.

Polychlorinated biphenyls (PCBs) are persistent industrial pollutants that have been linked to breast cancer progression. However, their molecular mechanism(s) are currently unclear. Our previous assessment suggested that the highly reactive PCB metabolite 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ) induces the metastasis of breast cancer. Here, our data illustrate that PCB29-pQ increases cancer stem cell (CSC) marker expression, resulting in an increase in the epithelial-mesenchymal transition (EMT) in MDA-MB-231 breast cancer cells; further, the Wnt/ß-catenin pathway also becomes activated by PCB29-pQ. When the Wnt/ß-catenin pathway is inhibited, the promotion of CSC properties and EMT by PCB29-pQ were accordingly reversed. In addition, the overproduction of reactive oxygen species (ROS) mediated by PCB29-pQ plays a key role in Wnt/ß-catenin activation. Collectively, our current data designated the regulatory role of Wnt/ß-catenin in PCB29-pQ-triggered acquisition of CSC properties and EMT.

Polychlorinated biphenyl quinone regulates MLKL phosphorylation that stimulates exosome biogenesis and secretion via a short negative feedback loop.

Polychlorinated biphenyls (PCBs) are one of the most refractory organic environmental pollutants that ubiquitous existence in nature. Due to the polymorphism of their metabolic pathway and corresponding downstream metabolites, PCBs' toxicities are complicated and need extended investigation. In the present study, we discovered a novel regulatory mechanism of PCB quinone metabolite-driven programmed cell death (PCD), namely, necroptosis. We first confirmed that PCB quinone induces cancerous HeLa and MDA-MB-231 cells necroptosis via the phosphorylation of mixed lineage kinase domain-like MLKL (p-MLKL). Then, we found that PCB quinone-stimulated p-MLKL enhances exosome biogenesis and secretion. Exosome interacts with p-MLKL and releases p-MLKL to the outside of the cell, and ultimately alleviating PCB quinone-induced necroptosis. The inhibition of exosome secretion by GW4869 significantly elevated necroptotic level, indicating the establishment of a short negative feedback loop of MLKL-exosome secretion upon PCB quinone challenge. Since exosome-mediated signaling showed great implications in various human diseases, this work may provide a new mechanism for PCBs-associated toxicity.

Polychlorinated Biphenyl Quinone Promotes Atherosclerosis through Lipid Accumulation and Endoplasmic Reticulum Stress via CD36.

Polychlorinated biphenyls (PCBs) are persistent organic environmental pollutants. According to previous epidemiological reports, PCBs exposure is highly related to atherosclerosis. However, studies of PCBs metabolites and atherosclerosis and corresponding mechanism studies are scarce. In this study, we evaluated the effect of 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ), a presumptive PCB metabolite, on atherosclerosis. Aortic plaques were increased in PCB29-pQ-treated ApoE-/- mice [intraperitoneally (i.p.) injection of 5 mg/kg body weight of PCB29-pQ once a week for 12 continuous weeks, high-fat feeding]. We observed lipids accumulation and the release of interleukin-1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) in ApoE-/- mice. In addition, we found that PCB29-pQ promoted the levels of total cholesterol, free cholesterol, triglyceride, and cholesteryl ester. Mechanism investigation indicated that PCB29-pQ induces the activation of three branches of endoplasmic reticulum (ER) stress response, that is, phosphorylated protein kinase R-like ER kinase (p-PERK), eukaryotic translation initiation factor 2α (eIF2α) and transcription factor 6 (ATF6), which is responsible for downstream necrosis. More importantly, we found the silence of CD36 is able to reverse PCB29-pQ-induced adverse effects completely. Overall, PCB29-pQ exposure resulted in lipid accumulation, ER stress response, apoptosis, and pro-inflammatory cytokines release via CD36, ultimately leading to atherosclerosis.