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.

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.

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.

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.

Polychlorinated Biphenyl Quinone Promotes Macrophage-Derived Foam Cell Formation.

Polychlorinated biphenyls (PCBs) are organic environmental pollutants that are accused of various toxic effects. PCB exposure is widely believed to be associated with atherosclerosis, but the underlying mechanisms are unclear. Although PCBs are easily metabolized, there is rarely information on the effects of their metabolites on atherosclerosis. Currently, we evaluate the effect of 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ) on the critical phase of atherosclerosis development, that is, the formation of macrophage-derived foam cells. We exposed Ox-LDL-induced RAW264.7 cells to 2.5 µM and 5 µM PCB29-pQ. Varieties of evidence have demonstrated that PCB29-pQ promotes foam cell formation and develops proinflammatory cascade and cell necroptosis. In detail, we observed that PCB29-pQ increased levels of total cholesterol (TC), free cholesterol (FC), triglyceride (TG), and cholesteryl ester (CE) by increasing the cholesterol influx and reducing the cholesterol efflux. Moreover, we found that PCB29-pQ induced inflammatory cytokines, such as tumor necrosis factor (TNF-α), interleukin 6 (IL-6), and IL-1ß, released by activating the mitogen-activated protein kinase (MAPK)-nuclear factor kappa B (NF-κB) inflammatory pathway. In addition, we demonstrated that PCB29-pQ induced cell necroptosis via receptor interacting protein kinases 1 and 3 (RIPK1/3) and a mixed-lineage kinase domain-like (MLKL) pathway. Finally, the overproduction of reactive oxygen species (ROS) by PCB29-pQ played significant roles in these processes, which could be reversed with an antioxidant. Overall, our results indicated that PCB29-pQ promoted the macrophage formation of foam cells, inflammation, and cell necroptosis.

Polybrominated Diphenyl Ethers Quinone Induces NCOA4-Mediated Ferritinophagy through Selectively Autophagic Degradation of Ferritin.

Polybrominated diphenyl ethers (PBDEs) have been detected ubiquitously in biological and environmental samples. Growing epidemiological data suggested the obvious correlation of PBDEs exposure with adverse health outcomes toward human beings, but exact molecular mechanism(s) are limited. Especially, the toxicological information regarding PBDEs metabolites is missing. Thereafter, this study intends to explore unidentified cell death modalities caused by PBDEs reactive quinone-type metabolite, PBDEQ. We found that PBDEQ induces autophagy in an ROS-dependent manner. Interestingly, the results indicated that PBDEQ degraded ferritin and activated a selective autophagy (termed as ferritinophagy) by using NCOA4 as its cargo receptor. These processes may further promote the release of iron and ROS. These results suggested the incidence of ferritinophagy induced by PBDEQ, which may contribute to PBDE exposure-caused diseases and dysfunctions.

Polychlorinated Biphenyl Quinone Induces Caspase 1-Mediated Pyroptosis through Induction of Pro-inflammatory HMGB1-TLR4-NLRP3-GSDMD Signal Axis.

Polychlorinated biphenyls (PCBs) are one of the most refractory environmental pollutants. Because of their ubiquitous existence in the biological systems (including human body), it is important to investigate their toxic behavior. Our previous findings demonstrated that a high reactive metabolite of PCB, namely PCB29-pQ, causes several programmed cell death (PCD) such as intrinsic/extrinsic apoptosis and autophagic cell death. The mechanistic study suggested the toxic actions of PCB29-pQ is largely related to its reactive oxygen species (ROS)-generation ability. Pyroptosis is a caspase 1-mediated pro-inflammatory PCD, which was discovered recently. The aim of this study is to seek the linkage between pyroptosis and PCB29-pQ exposures. We first confirmed that PCB29-pQ stimulates Hela cells to produce excess amounts of ROS. Then we found PCB29-pQ activates NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome that mediates caspase 1 activation. The activated caspase 1 (cleaved caspase 1) promotes gasdermin D (GSDMD) cleavage and translocation, which facilitates the release of intracellular inflammatory substances by forming membrane hole, ultimately leading cells to pyroptosis. PCB29-pQ-induced high-mobility group box 1 (HMGB1) release and subsequent binding to its receptors [toll-like receptor 2 (TLR2), TLR4, TLR9, and receptor for advanced glycation end products (RAGE)] are essential for the activation of NLRP3 inflammasome. The current study revealed pyroptosis as a new death mode induced by PCB29-pQ, which enriched the understanding of PCBs-induced toxicity and helped to prevent the toxic effects of residual PCBs in the environment.

Polybrominated Diphenyl Ethers Quinone Induced Parthanatos-like Cell Death through a Reactive Oxygen Species-Associated Poly(ADP-ribose) Polymerase 1 Signaling.

Polybrominated diphenyl ethers (PBDEs) are emerging organic environmental pollutants, which were accused of various toxic effects. Here, we studied the role of a potential PBDEs quinone metabolite, PBDEQ, on cytotoxicity, oxidative DNA damage, and the alterations of signal cascade in HeLa cells. PBDEQ exposure leads to reactive oxygen species (ROS) accumulation, mitochondrial membrane potential (MMP) loss, lactate dehydrogenase (LDH) release, increasing terminal transferase-mediated dUTP-biotin nick end labeling (TUNEL) positive foci, and the elevation of apoptosis rate. Furthermore, we showed PBDEQ exposure result in increased DNA migration, micronucleus frequency, and the promotion of 8-OHdG and phosphorylation of histone H2AX (γ-H2AX) levels. Mechanism study indicated that PBDEQ caused poly(ADP-ribose) polymerase 1 (PARP-1) activation and apoptosis-inducing factor (AIF) nuclear translocation. All together, these results confirmed the occurrence of parthanatos-like cell death upon PBDEQ exposure.

Atypical Gasdermin D and Mixed Lineage Kinase Domain-like Protein Leakage Aggravates Tetrachlorobenzoquinone-Induced Nod-like Receptor Protein 3 Inflammasome Activation.

Our previous study showed that tetrachlorobenzoquinone (TCBQ) mediated the activation of Nod-like receptor protein 3 (NLRP3) inflammasome, which involves K+ efflux, reactive oxygen species (ROS) production, and mitochondrial DNA damage. In addition, TCBQ down-regulates NLRP3 ubiquitination and promotes the activation of NLRP3 inflammasome. However, the induction of NLRP3 inflammasome by atypical pathways has not yet been characterized. Using human umbilical vein endothelial cells (HUVEC), we discovered that TCBQ activates caspase 1/4/5 and cleaves gasdermin D (GSDMD) into N-terminal and C-terminal cleavage products. In parallel, TCBQ also activates receptor interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like protein (MLKL) signaling pathways. The N-terminal fragments of GSDMD and MLKL translocate from cytoplasm to cell membrane and form oligomers and membrane pores on the cell membrane. The formation of membrane pores not only promotes the extracellular secretion of interleukin 1 beta (IL-1ß) but also affects cellular ion homeostasis, in particular promotes K+ outflow, which further activates NLRP3 inflammasome and aggravates cellular inflammation. These results indicated that GSDMD and MLKL play important roles in TCBQ-induced endothelial pro-inflammatory responses, which may point to potential therapeutic approaches for TCBQ-mediated toxicity.

Tetrachlorobenzoquinone-Induced Nrf2 Confers Neuron-like PC12 Cells Resistance to Endoplasmic Reticulum Stress via Regulating Glutathione Synthesis and Protein Thiol Homeostasis.

Our previous studies demonstrated that tetrachlorobenzoquinone (TCBQ) is toxic to neuron-like cells, which is related to endoplasmic reticulum (ER) stress-induced apoptosis. However, it remains unclear whether TCBQ causes the opening of cellular defense responses. Here we found that activation of nuclear factor erythroid-derived 2-like 2 (Nrf2) triggered an adaptive response against the neurotoxicity induced by TCBQ through the upregulation of intracellular glutathione (GSH) levels in rat pheochromocytoma PC12 cells. TCBQ upregulated the levels of GSH mainly by the following two ways: (i) Nrf2 activation induced the expression of cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11, also called xCT); (ii) Nrf2 activation resulted in increased the expression of glutamylcysteine ligase. GSH is involved in cell antioxidant ability and protein thiol homeostasis, especially in the ER. Therefore, GSH has the ability to inhibit ER stress and promote cell survival. Our data showed that decreasing GSH levels exacerbated TCBQ-induced depletion of protein-SH, particularly in the ER. Conversely, increasing GSH levels attenuated TCBQ-induced protein damage, degree of ER stress, and cell death. These findings demonstrated that GSH-inhibited cells were vulnerable to TCBQ-induced ER stress and apoptosis. Overall, our results analyzed the relationships between Nrf2 and ER stress in response to TCBQ and showed that activation of Nrf2-GSH played a protective role against TCBQ-induced ER stress-associated neurotoxicity via regulating GSH synthesis and protein thiol homeostasis.

Polychlorinated Biphenyl Quinones Promotes Breast Cancer Metastasis through Reactive Oxygen Species-Mediated Nuclear Factor κB-Matrix Metalloproteinase Signaling.

It is generally acknowledged that polychlorinated biphenyls (PCBs) exposure increased the incidence of cancer, however, the underlying mechanism(s) of PCBs-induced cancer metastasis are unclear. Although PCBs readily metabolize, little information is available regarding the effect of PCBs metabolites on cancer metastasis. Currently, we evaluate a highly reactive PCBs metabolite, 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ), relevant to exposure with mammary cancer metastasis. Multiple lines of evidence illustrated that PCB29-pQ induces breast cancer invasion and migration. In particular, this appearance is associated with a two-fold elevation of matrix metalloproteinases-2/-9 (MMP-2/-9) and extracellular nuclear factor kappa B (NF-κB), respectively. Our results clearly demonstrated the translocation of cytosolic NF-κB into the nucleus by a factor of about 2.4. We also revealed the activation of corresponding upstream signaling cascades phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt and p38 and extracellular regulated protein kinases (ERK) mitogen-activated protein kinase (MAPK) by factors of 3.15, 3.09 and 1.69, respectively. Moreover, there was a marked induction of reactive oxygen species (ROS) after a PCB29-pQ challenge and antioxidant treatment that markedly inhibited PCB29-pQ-mediated activation of these axis signaling. Collectively, our result suggested that PCB29-pQ induces breast cancer metastasis via ROS-dependent NF-κB-MMP signaling.

Influence of Waveform Characteristics on LiDAR Ranging Accuracy and Precision.

Time of flight (TOF) based light detection and ranging (LiDAR) is a technology for calculating distance between start/stop signals of time of flight. In lab-built LiDAR, two ranging systems for measuring flying time between start/stop signals include time-to-digital converter (TDC) that counts time between trigger signals and analog-to-digital converter (ADC) that processes the sampled start/stop pulses waveform for time estimation. We study the influence of waveform characteristics on range accuracy and precision of two kinds of ranging system. Comparing waveform based ranging (WR) with analog discrete return system based ranging (AR), a peak detection method (WR-PK) shows the best ranging performance because of less execution time, high ranging accuracy, and stable precision. Based on a novel statistic mathematical method maximal information coefficient (MIC), WR-PK precision has a high linear relationship with the received pulse width standard deviation. Thus keeping the received pulse width of measuring a constant distance as stable as possible can improve ranging precision.

Discovery of highly potent, selective, covalent inhibitors of JAK3.

A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information and a comparative study of several electrophilic warheads.

Influence of Time-Pickoff Circuit Parameters on LiDAR Range Precision.

A pulsed time-of-flight (TOF) measurement-based Light Detection and Ranging (LiDAR) system is more effective for medium-long range distances. As a key ranging unit, a time-pickoff circuit based on automatic gain control (AGC) and constant fraction discriminator (CFD) is designed to reduce the walk error and the timing jitter for obtaining the accurate time interval. Compared with Cramer-Rao lower bound (CRLB) and the estimation of the timing jitter, four parameters-based Monte Carlo simulations are established to show how the range precision is influenced by the parameters, including pulse amplitude, pulse width, attenuation fraction and delay time of the CFD. Experiments were carried out to verify the relationship between the range precision and three of the parameters, exclusing pulse width. It can be concluded that two parameters of the ranging circuit (attenuation fraction and delay time) were selected according to the ranging performance of the minimum pulse amplitude. The attenuation fraction should be selected in the range from 0.2 to 0.6 to achieve high range precision. The selection criterion of the time-pickoff circuit parameters is helpful for the ranging circuit design of TOF LiDAR system.

Discovery of pyrrolo[1,2-b]pyridazine-3-carboxamides as Janus kinase (JAK) inhibitors.

A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.

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.

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.

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.

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.

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.