Stage-Related Neurotoxicity of BPA in the Development of Zebrafish Embryos.

Bisphenol A (BPA) is one of the most widely produced chemicals in the world used in the production of epoxy resins and polycarbonate plastics. BPA is easily migrated from the outer packaging to the contents. Due to the lipophilic property, BPA is easily accumulated in organisms. Perinatal low-dose BPA exposure alters brain neural development in later generations. In this study, after BPA treatment, the spontaneous movement of zebrafish larvae from the cleavage period to the segmentation period (1-24 hpf) was significantly decreased, with speed decreasing by 18.97% and distance decreasing between 18.4 and 29.7% compared to controls. Transcriptomics analysis showed that 131 genes were significantly differentially expressed in the exposed group during the 1-24 hpf period, among which 39 genes were significantly upregulated and 92 genes were significantly downregulated. The GO enrichment analysis, gene function analysis and real-time quantitative PCR of differentially expressed genes showed that the mRNA level of guanine deaminase (cypin) decreased significantly in the 1-24 hpf period. Moreover, during the 1-24 hpf period, BPA exposure reduced guanine deaminase activity. Therefore, we confirmed that cypin is a key sensitive gene for BPA during this period. Finally, the cypin mRNA microinjection verified that the cypin level of zebrafish larvae was restored, leading to the restoration of the locomotor activity. Taken together, the current results show that the sensitive period of BPA to zebrafish embryos is from the cleavage period to the segmentation period (1-24 hpf), and cypin is a potential target for BPA-induced neurodevelopmental toxicity. This study provides a potential sensitive period and a potential target for the deep understanding of neurodevelopmental toxicity mechanisms caused by BPA.

The cytotoxicity of PM2.5 and its effect on the secretome of normal human bronchial epithelial cells.

Exposure to airborne fine particulate matter (PM2.5) induced various adverse health effects, such as metabolic syndrome, systemic inflammation, and respiratory disease. Many works have studied the effects of PM2.5 exposure on cells through intracellular proteomics analyses. However, changes of the extracellular proteome under PM2.5 exposure and its correlation with PM2.5-induced cytotoxicity still remain unclear. Herein, the cytotoxicity of PM2.5 on normal human bronchial epithelia cells (BEAS-2B cells) was evaluated, and the secretome profile of BEAS-2B cells before and after PM2.5 exposure was investigated. A total of 83 proteins (58 upregulated and 25 downregulated) were differentially expressed in extracellular space after PM2.5 treatment. Notably, we found that PM2.5 promoted the release of several pro-apoptotic factors and induced dysregulated secretion of extracellular matrix (ECM) constituents, showing that the abnormal extracellular environment attributed to PM2.5-induced cell damage. This study provided a secretome data for the deep understanding of the molecular mechanism underlying PM2.5-caused human bronchial epithelia cell damage.

Insights into the hepatotoxicity of pyrene and 1-chloropyrene using an integrated approach of metabolomics and transcriptomics.

The toxicity of pyrene (Pyr) and its chlorinated species have not be comprehensively and clearly elucidated. In this study, an integrated approach of metabolomics and transcriptomics were applied to evaluate the hepatotoxicity of Pyr and 1-chloropyrene (1-Cl-Pyr) at human exposure level, using human L02 hepatocytes. After 24 h exposure to Pyr and 1-Cl-Pyr at 5-500 nM, cell viability was not significantly changed. Transcriptomics results showed that exposure to Pyr and 1-Cl-Pyr at 5 and 50 nM obviously altered the gene expression profiles, but did not significantly induce the expression of genes strongly related to the activation of aryl hydrocarbon receptor (AhR), such as CYP1A1, CYP1B1, AHR, ARNT. Pyr and 1-Cl-Pyr both induced a notable metabolic perturbation to L02 cells. Glycerophospholipid metabolism was found to be the most significantly perturbed pathway after exposure to Pyr and 1-Cl-Pyr, indicating their potential damage to the cell membrane. The other significantly perturbed pathways were identified to be oxidative phosphorylation (OXPHOS), glycolysis, and fatty acid ß oxidation, all of which are related to energy production. Exposure to Pyr at 5 and 50 nM induced the up-regulation of fatty acid ß oxidation and OXPHOS. The similar result was observed after exposure to 5 nM 1-Cl-Pyr. In contrast, exposure to 50 nM 1-Cl-Pyr induced the down-regulation of OXPHOS by inhibiting the activity of complex I. The obtained results suggested that the modes of action of Pyr and 1-Cl-Pyr on energy production remarkably varied not only with molecular structure change but also with exposure concentration.

Transcriptomics and metabolomics analyses provide insights into the difference in toxicity of benzo[a]pyrene and 6-chlorobenzo[a]pyrene to human hepatic cells.

The toxicological information of chlorinated polycyclic aromatic hydrocarbons (Cl-PAHs), as derivatives of PAHs, is still relatively lacking. In this study, a combination of transcriptomics and metabolomics approach was adopted to explore the changes in toxicity to human L02 hepatocytes after chlorination of benzo[a]pyrene (B[a]P) at 6 position. In general, 6-Cl-B[a]P produced a stronger toxicity to human hepatic cells than did parent B[a]P. When exposure concentrations were 5 and 50 nM, 6-Cl-B[a]P caused a weaker transcriptomic perturbation relative to B[a]P, whereas a stronger metabolomic perturbation, a stronger oxidative stress and a stronger inhibition effect on cell viability were caused by 6-Cl-B[a]P than did parent B[a]P. Pathway enrichment analysis indicated that 6-Cl-B[a]P produced a more widely perturbation to metabolic pathways than did B[a]P. Although they both significantly impaired the function of mitochondrial electron transport chain (ETC), the exact mechanism is different. B[a]P suppressed the expression of 20 genes regulating mitochondrial ETC mainly via AhR activation. However, 6-Cl-B[a]P produced a stronger inhibition on the activities of complexes I and V than did B[a]P. Meanwhile, 6-Cl-B[a]P also exhibited a stronger inhibition effect on mitochondrial ß oxidation of fatty acid. Furthermore, 6-Cl-B[a]P and B[a]P both significantly disturbed the nucleotide metabolism, glycerophospholipid metabolism and amino acid metabolism in L02 cells.

Multi-omics analysis to reveal disorders of cell metabolism and integrin signaling pathways induced by PM2.5.

Atmospheric fine particle pollution is known to cause many adverse health effects. However, the potential mechanisms of PM2.5-induced cytotoxicity still needs further understanding. Herein, we integrated cytotoxicity, component profiling, metabolomics and proteomics data to deeply explain the biological responses of human bronchial epithelial cells exposed to PM2.5. We observed that PM2.5 caused cell cycle arrest, calcium influx, cell damage and further induced cell apoptosis. The contents of heavy metals and 4-6 rings PAHs in PM2.5 were positively correlated with intracellular ROS, indicating that they might be the important components to induce the above cytotoxicity. Integrated metabolomics and proteomics analysis revealed the significant alterations of many metabolic processes, such as glycolysis, the citric acid cycle, amino acid metabolism and lipid metabolism. Notably, we found that PM2.5 inhibited the integrin signaling pathway, including down-regulating the protein expression of integrins and the phosphorylation of downstream signaling kinases, which might ultimately affect cell cycle progression, cell metabolism and apoptosis. This study provided a comprehensive data resource for the deep understanding of biological toxicity mechanisms caused by atmospheric fine particles in human lung-bronchial epithelium cells.

Effect of short-chain chlorinated paraffins on metabolic profiling of male SD rats.

The toxic effect of high-dose of short-chain chlorinated paraffins (SCCPs) has been extensively studied, however the possible health risks induced by SCCPs at low-dose remain largely unknown. In this study, a comprehensive toxicology analysis of SCCPs was conducted with the exposure levels from the environmental dose to the Lowest Observed Adverse Effect Level (LOAEL) of 100 mg/kg/day. General toxicology analysis revealed inconspicuous toxicity of the environmental dose of SCCPs, high dose SCCP exposure inhibited the growth rate and increased the liver weight of rat. Metabolomics analysis indicated that SCCP-induced toxicity was triggered at environmentally relevant doses. First, inhibition of energy metabolism was observed with the decrease in blood glucose and the dysfunction of TCA cycle, which may have contributed to lower body weight gain in rats exposed to a high dose of SCCPs. Second, the increase of free fatty acids indicated the acceleration of lipid metabolism to compensate for the energy deficiency caused by hypoglycemia. Lipid oxidative metabolism inevitably leads to oxidative stress and stimulates the up-regulation of antioxidant metabolites such as GSH and GSSH. The up-regulation of polyunsaturated fatty acids (PUFAs) and phospholipids composed of arachidonic acid indicates the occurrence of inflammation. Dysfunction of lipid metabolism can be an indicator of SCCP-induced liver injury.

The effect of toxic components on metabolomic response of male SD rats exposed to fine particulate matter.

PM2.5 pollution was associated with numerous adverse health effects. However, PM2.5 induced toxic effects and the relationships with toxic components remain largely unknown. To evaluate the metabolic toxicity of PM2.5 at environmentally relevant doses, investigate the seasonal variation of PM2.5 induced toxicity and the relationship with toxic components, a combination of general pathophysiological tests and metabolomics analysis was conducted in this study to explore the response of SD rats to PM2.5 exposure. The result of general toxicology analysis revealed unconspicuous toxicity of PM2.5 under environmental dose, but winter PM2.5 at high dose caused severe histopathological damage to lung. Metabolomic analysis highlighted significant metabolic disorder induced by PM2.5 even at environmentally relevant doses. Lipid metabolism and GSH metabolism were primarily influenced by PM2.5 exposure due to the high levels of heavy metals. In addition, high levels of organic compounds such as PAHs, PCBs and PCDD/Fs in winter PM2.5 bring multiple overlaps on the toxic pathways, resulting in larger pulmonary toxicity and metabolic toxicity in rats than summer.

Comparing the disrupting effects of short-, medium- and long-chain chlorinated Paraffins on cell viability and metabolism.

With the phasing out of short-chain chlorinated paraffins (SCCPs), the production and emissions of medium- and long-chain chlorinated paraffins (MCCPs and LCCPs) are expected to increase. In this study, cell viability assay and pseudotargeted metabolomics approach were adopted to define and compare the toxic effects induced by SCCPs, MCCPs and LCCPs. The dose response curves indicated that three CP mixtures with comparable chlorine contents produced similar inhibitory effects on cell viability. At exposure concentration of 100 µg/L, three CP mixtures all induced significant increases in levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and a significant reduction in level of adenosine triphosphate production (ATP), and produced similar impact intensities on overall metabolism. A stronger perturbation in phospholipid and fatty acid metabolism was observed in all CP exposure groups. In comparison with SCCPs and MCCPs, LCCPs produced a stronger suppressive effect on amino acid transport across cell membrane and induced an opposite effect on purine metabolism. Furthermore, the toxicity mechanism and possible health risks of the three types of CPs were discussed. MCCPs shared the most similar cytotoxicity and metabolic perturbation with SCCPs, suggesting that there should be concern about using MCCPs as alternatives to SCCPs.

Negative Capacitance beyond Ferroelectric Switches.

Negative capacitance transistors are a unique class of switches capable of operation beyond the Boltzmann limit to realize subthermionic switching. To date, the negative capacitance effect has been predominantly attributed to devices employing an unstable insulator with ferroelectric properties, exhibiting a two-well energy landscape, in accordance with the Landau theory. The theory and operation of a solid electrolyte field effect transistor (SE-FET) of subthreshold swing less than 60 mV/dec in the absence of a ferroelectric gate dielectric are demonstrated in this work. Unlike ferroelectric FETs that rely on a sudden switching of dipoles to achieve negative capacitance, we demonstrate a distinctive mechanism that relies on the accumulation and dispersion of ions at the interfaces of the oxide, leading to a subthreshold slope (SS) as low as 26 mV/dec in these samples. The frequency of operation of these unscaled devices lies in a few millihertz because at higher or lower frequencies, the ions in the insulator are either too fast or too slow to produce voltage amplification. This is unlike Landau switches, where the SS remains below 60 mV/dec even under quasi-static sweep of the gate bias. The proposed FETs show a higher on-current with a thicker oxide in the entire range of gate voltage, clearly distinguishing their scaling laws from those of ferroelectric FETs. Our theory, validated with experiment, demonstrates a new class of devices capable of negative capacitance that opens up alternate methods of steep switching beyond the traditional approach of ferroelectric or memristive FETs.

Diffusion-Controlled Faradaic Charge Storage in High-Performance Solid Electrolyte-Gated Zinc Oxide Thin-Film Transistors.

An electrochemical device capable of manifesting reversible charge storage at the interface of an active layer offers formidable advantages, such as low switching energy and long retention time, in realizing synaptic behavior for ultralow power neuromorphic systems. Contrary to a supercapacitor-based field-effect device that is prone to low memory retention due to fast discharge, a solid electrolyte-gated ZnO thin-film device exhibiting a battery-controlled charge storage mechanism via mobile charges at its interface with tantalum oxide is demonstrated. Analysis via cyclic voltammetry and chronoamperometry uniquely distinguishes the battery behavior of these devices, with an electromotive force generated due to polarization of charges strongly dependent on the scan rate of the applied voltage. The Faradaic-type diffusion-controlled charge storage mechanism exhibited by these devices is capable of delivering robust enhancement in the channel conductance and leads to a superior ON-OFF ratio of 108-109. The nonvolatile behavior of the interface charge storage and slow diffusion of ions is utilized in efficiently emulating spike timing-dependent plasticity (STDP) at similar time scales of biological synapses and unveils the possibility of STDP behavior using multiple in-plane gates that alleviate additional requirement of waveform-shaping circuits.

Short-chain chlorinated paraffins (SCCPs) induced thyroid disruption by enhancement of hepatic thyroid hormone influx and degradation in male Sprague Dawley rats.

Short-chain chlorinated paraffins (SCCPs) are known to disturb thyroid hormone (TH) homeostasis in rodents. However, the mechanism remains to be fully characterized. In this study, male Sprague Dawley rats received SCCPs (0, 1, 10, or 100mg/kg/day) via gavage once a day for consecutive 28days. Plasma and hepatic TH concentrations, thyrocyte structure, as well as thyroid and hepatic mRNA and protein levels of genes associated with TH homeostasis were examined. Moreover, we performed molecular docking to predict interactions between constitutive androstane receptor (CAR), a key regulator in xenobiotic-induced TH metabolism, with different SCCP molecules. Exposure to SCCPs significantly decreased the circulating free thyroxine (T4) and triiodothyronine (T3) levels, but increased thyroid-stimulating hormone (TSH) levels by a feedback mechanism. Decreased hepatic T4 and increased hepatic T3 levels were also seen after 100mg/kg/day SCCPs exposure. SCCPs didn't show any significant effects on the expression of thyroid TH synthesis genes or thyrocyte structure. However, stimulation effects were observed for mRNA and protein levels of hepatic uridine diphosphoglucuronosyl transferase (UGT) 1A1 and organic anion transporter 2, suggesting an accelerated TH metabolism in rat liver. The increased cytochrome P450 2B1 but not 1A1 mRNA and protein levels indicated that the CAR signaling was activated by SCCPs exposure. According to docking analysis, SCCPs form hydrophobic interactions with CAR and the binding affinity shows dependency on chlorine content. Overall, our data showed that CAR implicated enhancement of hepatic TH influx and degradation could be the main cause for SCCPs induced TH deficiency in male rats.

Atrazine Causes Autophagy- and Apoptosis-Related Neurodegenerative Effects in Dopaminergic Neurons in the Rat Nigrostriatal Dopaminergic System.

Atrazine (2-chloro-4-ethytlamino-6-isopropylamine-1,3,5-triazine; ATR) is widely used as a broad-spectrum herbicide. Animal studies have demonstrated that ATR exposure can cause cell death in dopaminergic neurons. The molecular mechanisms underlying ATR-induced neuronal cell death, however, are unknown. In this study, we investigated the autophagy and apoptosis induced by ATR in dopaminergic neurons in vivo. Wistar rats were administered with ATR at doses of 10, 50 and 100 mg/kg body weight by oral gavage for three months. In terms of histopathology, the expression of autophagy- and apoptosis-related genes as well as proteins related to the Beclin-1/B-cell lymphoma 2 (Bcl-2) autophagy and apoptosis pathways were examined in the rat nigrostriatal dopaminergic system. We observed degenerative micromorphology indicative of neuronal apoptosis and mitochondrial autophagy by electron microscopy in ATR-exposed rat striatum. The rat ventral mesencephalon in the ATR-exposed groups also showed increased expression of Beclin-1, LC3-II, Bax and Caspase-9, and decreased expression of tyrosine hydroxylase (TH), Bcl-xl and Bcl-2. These findings indicate that ATR may induce autophagy- and apoptosis-related changes in doparminergic neurons. Furthermore, this induction may be regulated by the Beclin-1 and Bcl-2 autophagy and apoptosis pathways, and this may help to better understand the mechanism underlying the neurotoxicity of ATR.