Potential Mechanisms Of Toxicity Research Articles

Potential Toxic Mechanisms of Neonicotinoid Insecticides in Rice: Inhibiting Auxin-Mediated Signal Transduction.

Inappropriate application of pesticides not only causes sub-lethal effects on ecosystem service providers but also reduces crop yield and quality. As a xenobiotic signal molecule, pesticides may interact with signal transduction receptors in crops, resulting in oxidative damage and even metabolic perturbations. We discovered that three neonicotinoid insecticides (NIs), namely, imidacloprid, thiamethoxam, and clothianidin, at 0.06-0.12 kg ai/ha significantly inhibited the auxin signal pathway in rice leaves, thereby reducing the intracellular auxin (IAA) content. Molecular simulation further confirmed that NIs occupied the binding site where auxin transporter-like proteins 1 (LAX11) and 2 (LAX12), in which Thr253 and Asn66 of LAX11, as well as Thr244 and Asn57 of LAX12, were bound to the nitroguanidine of NIs via H-bonds. Meanwhile, Asn66 of LAX11 and Asn57 of LAX12 interacted with nitroguanidine via aromatic H-bonds. Moreover, phenylpropanoid biosynthesis was significantly disturbed because of the inhibited auxin signal pathway. Notably, peroxidase-coding genes were downregulated with a maximum value greater than 10-fold, resulting in decreased antioxidant metabolites flavone (37.82%) and lignin content (20.15%). Ultimately, rice biomass was reduced by up to 25.41% due to the decline in IAA content and antioxidant capacity. This study deeply explored the molecular mechanism of metabolic perturbations in crops stressed by pesticides, thus providing a scientific basis for pesticide environmental risk assessment and agricultural product safety.

Early exposure to wildfire smoke can lead to birth defects.

The results of two previously published reports of the events and impacts of the Campfire wildfire smoke exposure that occurred in California in 2018 are amplified from the point of view of the potential toxic mechanism involved. The Campfire wildfire led to the exposure of a breeding colony of macaque monkeys (Macaca mulatta) during the peak of their breeding season in 2018-2019. Considering the timing, adverse effects, and endocrine implications reported, the cumulative evidence points to an early toxic sensitive period that can lead to birth defects in higher primates and human pregnancies. This deeper inspection of the published observations provides important caveats and useful guidance for future investigators. The unique higher primate placental-adrenal-brain axis may limit the use of many traditional toxicologic approaches. Retrospective neurological evaluations of human fetuses exposed to air pollutants during organogenesis and subsequent retrospective characterization of air samples using in vitro and animal models may be the best procedures to follow.

Sodium valproate exposure influences the expression of pparg in the zebrafish model.

Valproic acid (VPA) is an anti-epileptic drug used alone or in combination with other medications to treat seizures, mania, and bipolar disorder. VPA recognized as a teratogenic chemical can cause severe birth defects mainly affecting the brain and spinal cord when administered during pregnancy. However, the potential mechanisms of developmental toxicity are still less studied, and in the present study, the influence of VPA exposure was evaluated on zebrafish early-life stages. Zebrafish were exposed to two sublethal concentrations of sodium valproate (SV) (0.06 mM and 0.15 mM) from 24 hours post-fertilization (hpf) to 96 hpf and the SV teratogenic potential was investigated through morphometric analysis of zebrafish larvae combined with the evaluation of cartilage profile. Moreover, the effect of SV on the transcription level of pparg was also performed. The results of the study showed the teratogenic potential of SV, which disrupts the morphometric signature of the head and body. The marked distortion of cartilage structures was paralleled to a malformation of telencephalon and optic tectum in both concentrations suggesting a high teratogen effect of SV on the brain. These data were further confirmed by the increased expression of pparg in the zebrafish head. Overall, the present study confirms the teratogenic activity of SV in the zebrafish model and, for the first time, points out the potential protective role of pparg in the SV dose-dependent toxicity.

Effects of acute exposure to amisulbrom on retinal development in zebrafish (Danio rerio) embryos.

Amisulbrom is an oomycete-specific fungicide that was developed by Nissan Chemical Industries Limited. The exposure of developing zebrafish embryo to amisulbrom caused disorders in the visual phototransduction system. However, the potential toxic mechanisms of amisulbrom on retinal development remains unclear. The research purpose of this study was to evaluate the adverse effects of amisulbrom on retinal development in a model organism, the zebrafish. Zebrafish embryos were treated with 0, 0.0075, 0.075, or 0.75μM amisulbrom from 3h post-fertilization (hpf) to 72 hpf. Compared with the control group, amisulbrom-treated zebrafish embryos displayed phenotypic microphthalmia, dysregulation of gene transcription levels (alcama, prox1a, sox2, vsx1, rho, bluops, rdops, uvops, and grops) related to the retinal cell layer differentiation, and increased retinal apoptosis. In addition, the content of glutathione and malondialdehyde increased significantly after exposure to amisulbrom. Overall, our data demonstrate the toxicity of amisulbrom to eye development, which will help to assess the potential ecotoxicological impacts posed by amisulbrom to aquatic species.

Network Pharmacology and Experimental Verification to Unveil the Mechanism of N-Methyl-D-Aspartic Acid Rescue Humantenirine-Induced Excitotoxicity

Gelsemium is a medicinal plant that has been used to treat various diseases, but it is also well-known for its high toxicity. Complex alkaloids are considered the main poisonous components in Gelsemium. However, the toxic mechanism of Gelsemium remains ambiguous. In this work, network pharmacology and experimental verification were combined to systematically explore the specific mechanism of Gelsemium toxicity. The alkaloid compounds and candidate targets of Gelsemium, as well as related targets of excitotoxicity, were collected from public databases. The crucial targets were determined by constructing a protein-protein interaction (PPI) network. Subsequently, Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore the bioprocesses and signaling pathways involved in the excitotoxicity corresponding to alkaloids in Gelsemium. Then, the binding affinity between the main poisonous alkaloids and key targets was verified by molecular docking. Finally, animal experiments were conducted to further evaluate the potential mechanisms of Gelsemium toxicity. A total of 85 alkaloids in Gelsemium associated with 214 excitotoxicity-related targets were predicted by network pharmacology. Functional analysis showed that the toxicity of Gelsemium was mainly related to the protein phosphorylation reaction and plasma membrane function. There were also 164 pathways involved in the toxic mechanism, such as the calcium signaling pathway and MAPK signaling pathway. Molecular docking showed that alkaloids have high affinity with core targets, including MAPK3, SRC, MAPK1, NMDAR2B and NMDAR2A. In addition, the difference of binding affinity may be the basis of toxicity differences among different alkaloids. Humantenirine showed significant sex differences, and the LD50 values of female and male mice were 0.071 mg·kg-1 and 0.149 mg·kg-1, respectively. Furthermore, we found that N-methyl-D-aspartic acid (NMDA), a specific NMDA receptor agonist, could significantly increase the survival rate of acute humantenirine-poisoned mice. The results also show that humantenirine could upregulate the phosphorylation level of MAPK3/1 and decrease ATP content and mitochondrial membrane potential in hippocampal tissue, while NMDA could rescue humantenirine-induced excitotoxicity by restoring the function of mitochondria. This study revealed the toxic components and potential toxic mechanism of Gelsemium. These findings provide a theoretical basis for further study of the toxic mechanism of Gelsemium and potential therapeutic strategies for Gelsemium poisoning.

Titanium Dioxide Nanoparticles Altered the lncRNA Expression Profile in Human Lung Cells.

Respiration is considered to be the main occupational or environmental exposure pathway of titanium dioxide nanoparticles (TiO2 NPs), and the lung is considered to be the target organ of respiratory exposure; however, the mechanism of respiratory toxicity is not fully understood. In this study, the effect of TiO2 NPs on the expression profile of long non-coding RNA (lncRNA) in bronchial epithelial cells (BEAS-2B) was investigated to understand their potential toxic mechanism. BEAS-2B cells were treated with 100 μg/mL TiO2 NPs for 48 h, then RNA sequencing was performed to screen the differential lncRNAs compared with the control group, and the enrichment pathways of the differentially expressed lncRNAs were further analyzed using the Kyoto Encyclopedia of Genes and Genomes (KEGG). The results identified a total of 45,769 lncRNAs, and 277 different lncRNAs were screened. KEGG pathway analysis showed that the targeted mRNAs of these different lncRNAs were enriched in the pyrimidine metabolism pathway. This work demonstrates that TiO2 NPs could alter the lncRNA expression profile in BEAS-2B cells, and epigenetics may play a role in the mechanism of respiratory toxicity induced by TiO2 NPs.

Association between uterine toxicity induced by chlorpyrifos and downregulation of heparin-binding epidermal growth factor and L-selectin genes.

Various factors are effective in reducing the fertility rate. This experiment aimed to investigate chlorpyrifos (CPF), an organophosphate, that could alter the structure of the uterus and the molecules involved in parental and fetal. CPF was injected intraperitoneally in thirty mice for five days in a week (six weeks). The animals were euthanized on the 5th day of gestation, then their blood and uterus were collected for biochemical and histopathological assays. Exposure to CPF resulted in a significant reduction in maternal weight gain and the number of litters. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were significantly increased in blood serum of the CPF group compared with the control. The number of uterus glands, endometrium thickness, and the uterine cavity were changed following CPF injection. Additional investigation indicated that the expressions of L-selectin, L-selectin ligand, and heparin-binding epidermal growth factor (HB-EGF) as initial adhesion of mice blastocysts and maternal endometrium biomarkers were downregulated in the CPF group. Nevertheless, any mortality and abnormal clinical symptoms were not observed in the treated mice. This study revealed a potential molecular mechanism of continuous CPF-induced toxicity in fetal-maternal attachment without clinical symptoms.

Gene expression profiling of human macrophages after graphene oxide and graphene nanoplatelets treatment reveals particle-specific regulation of pathways

Graphene and its derivatives are attractive materials envisaged to enable a wealth of novel applications in many fields including energy, electronics, composite materials or health. A comprehensive understanding of the potential adverse effects of graphene-related materials (GRM) in humans is a prerequisite to the safe use of these promising materials. Here, we exploited gene expression profiling to identify transcriptional responses and toxicity pathways induced by graphene oxide (GO) and graphene nanoplatelets (GNP) in human macrophages. Primary human monocyte-derived macrophages (MDM) and a human macrophage cell line, i.e. differentiated THP-1 cells, were exposed to 5 or 20 μg/mL GO and GNP for 6 and 24 h to capture early and more persistent acute responses at realistic or slightly overdose concentrations. GO and GNP induced time-, dose- and macrophage type-specific differential expression of a substantial number of genes with some overlap between the two GRM types (up to 384 genes (9.6%) or 447 genes (20.4%) in THP-1 or MDM, respectively) but also a high number of genes exclusively deregulated from each material type. Furthermore, GRM responses on gene expression were highly different from those induced by inflammogenic material crystalline quartz (maximum of 64 (2.3%) or 318 (11.3%) common genes for MDM treated with 20 μg/mL GO and GNP, respectively). Further bioinformatics analysis revealed that GNP predominantly activated genes controlling inflammatory and apoptotic pathways whereas GO showed only limited inflammatory responses. Interestingly, both GRM affected the expression of genes related to antigen processing and presentation and in addition, GO activated pathways of neutrophil activation, degranulation and immunity in MDM. Overall, this study provides an extensive resource of potential toxicity mechanisms for future safety assessment of GRM in more advanced model systems to verify if the observed changes in gene expression in human macrophages could lead to long-term consequences on human health.

Mass spectrometry imaging advances and application in pharmaceutical research

Mass spectrometry imaging (MSI) has been shown to be a valuable tool through nearly every stage of the preclinical drug research and development (R&D) pipeline, and even to the early phase of clinical pharmaceutical evaluation. MSI can specifically resolve distributions of a parent drug and its metabolic products across dosed specimens without loss of spatial information, thus facilitating the direct observation of a drug’s pharmacokinetic processes, such as absorption, distribution, metabolism, and excretion. MSI can simultaneously visualize hundreds of phenotype molecules, including proteins, glycans, metabolites, and lipids, which have unique distribution patterns and biofunctions across different physiologic regions. This featured specificity in the chemical and physical spaces empowers MSI as an ideal analytical technique in exploring a drug’s pharmacodynamic properties, including in vitro/in vivo efficacy, safety, potential toxicity, and possible molecular mechanism. The application of MSI in pharmaceutical research has also been expanded from the conventional dosed tissue analysis to the front end of the preclinical drug R&D pipeline, such as investigating the structure-activity relationship, high-throughput in vitro screening, and ex vivo studies on single cells, organoids, or tumor spheroids. This review summarizes MSI application in pharmaceutical research accompanied by its technical and methodologic advances serving this central demand.

Cytotoxicity and apoptosis induction of copper oxide-reduced graphene oxide nanocomposites in normal rat kidney cells

Copper oxide-reduced graphene oxide nanocomposites (CuO-rGO NCs) have received great attention from researchers due to their exceptional physicochemical properties that cannot be achieved by a single composition. CuO-rGO NCs have the potential to be used in diverse fields including agriculture, cosmetic, textile, the food industry, and biomedicine. The growing application and production of CuO-rGO NCs raises the concern of their effects on human and the environmental health. Knowledge on the toxicological response of CuO-rGO NCs in biological systems is scarce. This study was aimed to explore the cytotoxicity and apoptosis response of CuO-rGO NCs in normal rat kidney cells (NRR52E). CuO-rGO NCs was synthesized by a simple hydrothermal method using copper nitrate and graphene oxide (GO) as precursors. X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), and energy dispersive X-ray spectroscopy (EDS) confirmed the preparation of CuO-rGO NCs with high crystallinity, polygonal shape, smooth surface morphology. Besides, CuO nanoparticles were tightly anchored on rGO nanosheets. Biological results showed that CuO-rGO NCs induce a dose-dependent cytotoxicity in NRK52E cells evident by cell viability reduction and irregular cellular morphology. Fluorescent microscopic examination of 2,7-dichlorofluorescin probe showed that CuO-rGO NCs generate intracellular reactive oxygen species (ROS) in NRK52E cells. Acridine orange/ethidium bromide dual staining depicted that number of orange-red stained cells (apoptotic cells) increases with increasing concentration of CuO-rGO NCs. The 4′, 6-diamidino-2-phenylindole (DAPI) fluorescent staining exhibited that CuO-rGO NCs induce chromosomal condensation while normal-shaped nuclei were observed in the control cells. In cell cycle analysis, cells exposed to CuO-rGO NCs demonstrated significantly higher accumulation of apoptotic cells in subG1 phase. Altogether, we observed that CuO-rGO NCs induce cytotoxicity, ROS generation, and apoptosis in NRK52E cells. This preliminary study warrants future research to evaluate the potential mechanisms of CuO-rGO NCs toxicity at molecular level.

Potential mechanism of humic acid attenuating toxicity of Pb2+ and Cd2+ in Vallisneria natans

Humic substances are widely present in aquatic environments. Due to the high affinity of humic substances for metals, the interactions have been particularly studied. To assess the effect of humic acid (HA) on submerged macrophytes and biofilms exposed to heavy metal stress, Vallisneria natans was exposed to solutions containing different concentrations of HA (0.5–2.0 mg·L−1), Pb2+ (1 mg·L−1) and Cd2+ (1 mg·L−1). Results suggested that HA positively affected the plant growth and alleviated toxicity by complexing with metals. HA increased the accumulation of metals in plant tissues and effectively induced antioxidant responses and protein synthesis. It was also noted that the exposure of HA and metals promoted the abundance and altered the structure of microbial communities in biofilms. Moreover, the positive effects of HA were considered to be related to the expression of related genes resulting from altered DNA methylation levels, which were mainly reflected in the altered type of demethylation. These results demonstrate that HA has a protective effect against heavy metal stress in Vallisneria natans by inducing effective defense mechanisms, altering biofilms and DNA methylation patterns in aquatic ecosystems.

Mitochondrial toxicants in Xian-Ling-Gu-Bao induce liver injury by regulating the PI3K/mTOR signaling pathway: an in vitro study

BackgroundDrug-induced mitochondrial toxicity is thought to be a common mechanism of drug hepatotoxicity. Xian-Ling-Gu-Bao (XLGB) oral preparation is a commonly used drug for osteoporosis in China. Classical safety evaluation studies have shown that the entire preparation and six Chinese herbal medicines have high safety, but the incidence of drug-induced liver damage due to XLGB remains high, the mechanism and toxic substances causing liver injury are still unclear. The purpose of this study is to identify compounds with potential mitochondrial liabilities in XLGB, and to clarify their underlying mechanisms and related pathways.MethodsThe mitochondrial function analysis was performed using an extracellular flux assay, which simultaneously monitored both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Through network pharmacology and in vitro experimental verification, the potential protein targets, signaling pathways and molecular mechanism of mitochondrial toxicity have been studied.ResultsWe observed a significant decrease in mitochondrial respiration of Psoraleae Fructus and its five compounds in fundamental bioenergetics parameters such as basal respiration, ATP-linked production and maximal respiration, indicating mitochondrial dysfunction. The network pharmacology results showed that the influence of XLGB on mitochondrial dysfunction was closely related to PI3K-Akt signaling pathway, mTOR signaling pathway and Apoptosis. Western blot showed that the levels of mTOR, p-mTOR (Ser2448), Raptor, PI3K (p110α), Beclin 1, ATG5 and Caspase-9 were up-regulated after treatment with psoralidin, psoralen and bavachin, and the expression of Bcl-2 was down-regulated after bavachinin treatment.ConclusionsThe hepatotoxicity of XLGB is associated with mitochondrial dysfunction. Five compounds in Psoraleae Fructus showed mitochondrial damage, they are psoralidin, isobavachalcone, bavachinin, bavachin and psoralen, especially psoralidin showed significant reduction in reserve capacity and respiratory control ratios. The molecular mechanism is related to the activation of PI3K/mTOR signaling pathway to inhibit autophagy and induce mitochondrial apoptosis.

Toxic Effects and Mechanism of Pefloxacin on the Early Life Stage of Zebrafish (Danio rerio)

Pefloxacin (PFLX) is a type of fluoroquinolone (FQ) that has been widely used in aquaculture and animal husbandry. It is also a new kind of pseudo-persistent pollutant, which has some toxic effects. In this study, zebrafish (Danio rerio) embryos were used as exposure models to analyze the toxicity of PFLX. The results showed that PFLX was absorbed on the outer membrane surface at the beginning, and then a few PFLX slowly entered the cytoplasm. The adsorption complied with the Langmuir isotherm adsorption model. The surface morphology of the embryonic membrane was changed. PFLX exposure had no effect on fetal autonomous movement, but it significantly inhibited the embryo hatching rate. After PFLX exposure, the embryo and larval survival rates showed a clear dose–effect relationship. Though PFLX exposure did not cause teratogenic toxicity, it still affected cardiovascular function. The potential toxicity mechanism and developmental toxicity of PFLX to zebrafish were revealed. These results could be important for studies concerning FQ toxicology.

Genome-wide DNA methylation pattern in whole blood of patients with coal-burning arsenic poisoning

Exposure to coal-burning arsenic leads to an increased risk of cancer, multi-systems damage and chronic diseases, with DNA methylation one potential mechanism of arsenic toxicity. There are few studies on genome-wide methylation in the coal-burning arsenic poisoning population. Illumina 850 K methylation beadchip is the most suitable technology for DNA methylation of epigenome-wide association analysis. This study used 850 K to detect changes in Genome-wide DNA methylation in whole blood samples of 12 patients with coal-burning arsenic poisoning ( Arsenic poisoning group) and four healthy control participants (Healthy control group). There is clearly abnormal genome-wide DNA methylation in coal-burning arsenic poisoning, with 647 significantly different methylation positions, 524 different methylation regions and 335 significantly different methylation genes in arsenic poisoning patients compared with healthy controls. Further functional analysis of Gene ontology (GO) and Kyoto encyclopedia of genes (KEGG) found 592 GO items and 131 KEGG pathways between patients of coal-burning arsenic poisoning and healthy control. Then, analysis of gene degree and combined-score identified NAPRT1, NT5C3B, NEDD4L, SLC22A3 and RAB11B as target genes. Further validation by qRT-PCR indicates that mRNA expression of five genes changes significantly in the arsenic poisoning group (n = 72) compared to the healthy control group (n = 72). These results showed the genome-wide methylation pattern and highlighted five critical genes within the coal-burning arsenic poisoning population that involve Nicotinate and nicotinamide metabolism, Choline metabolism in cancer, and Ubiquitin mediated proteolysis. Next, the methylation profile of coal burning arsenic poisoning will be further excavation and the mechanism of coal burning arsenic poisoning will be further explored from five genes related pathways and functions.

Toxic releases and exposure assessment: A multi-endpoint approach in fish for ferrocene toxicity

Fe2+ in ferrocene facilities the oxidation. Based on this phenomenon, increased iron (Fe) level in freshwater ecosystems is thought as an important environmental problem in many geographic regions. In addition to increased mobilization of Fe from sediment due to changes in land use, mining, industrial activity, and elevated acid deposition are also proposed to be possible factors contributing to the increased Fe loading in freshwater environments. Ferrocene is useful in the modern organometallic chemistry industry due to its versatile applications. In this study, the toxicity potential and related toxicity mechanisms of acute ferrocene exposure as well as the protective potential of borax supplementation against ferrocene were investigated in rainbow trout during 96 h under semi-static conditions. In target tissues multiplexed endpoints of hematological indices, genotoxicity, oxidative stress response, DNA damage and apoptosis levels, as well as tumor necrosis factor alpha, and interleukin-6 activities were assessed in blood tissue. In liver tissue, in addition to the parameters studied in blood tissue (except cortisol), the nuclear factor erythroid-2, which regulates the expression of detoxification enzymes, was investigated.When the results obtained from blood analyzes were examined, ferrocen treatment caused different reactions (increase/decrease) in blood indexes, and these findings were confirmed by MN tests. In ferrocene-induced hematoxicite, the healing effect of borax application has been observed to increase inhibited values and decrease in indexes with increasing tendencies. Besides, this hematoxicity was also supported by cortisol increases. Our findings showed that ferrocene inhibited antioxidant enzyme activities and increased lipid peroxidation, 8-OH-dG, caspase 3, TNF-α, and IL-6 levels in both blood and liver tissues. Similarly, cortisol level (in blood tissue) and Nrf-2 level (in liver tissue) increased with ferrocene application. In the ferrocen+borax group, the MDA level decreased 11 % at the end of the 96th hour compared to the 48th hour, and the Nrf2 level increased 9 %. In general, enzyme inhibitions in blood and liver tissues have shown that ferrocen-mediated toxicity occurs in induced ROS, DNA damage, apoptos activity, and BX applications have a positive effect on the correction of toxicity in the direction of hormesis.In a conclusion, the present study suggested that borax migt exhibite ameliorative potential against ferrocene-induced toxicity in O. mykiss blood and liver via regulating the ROS/TNF-α/Nrf-2 pathway.

Ozone mechanism, kinetics, and toxicity studies of halophenols: Theoretical calculation combined with toxicity experiment

Aromatic disinfection by-products (DBPs), which are generally more toxic than aliphatic DBPs, have attracted increasing attention. The toxicity of 13 typical halophenols on Scenedesmus obliquus was experimentally investigated, and the ozonation mechanism and kinetics of representative halophenols were further studied by quantum chemical calculations. The results showed that the EC50 values of halophenols ranged from 2.74 to 60.23 mg/L, and their toxicity ranked as follows: di-halogenated phenols > mono-halogenated phenols, mixed halogen-substituted phenols > single halogen-substituted phenols, and iodophenols > bromophenols > chlorophenols. The toxicity of halophenols was well described by the electronegativity index (ω) as lg(EC50)−1 = 6.228ω – 3.869, indicating halophenols capturing electrons as their potential toxicity mechanism. The reactions of O3 with halophenolate anions were dominated by three mechanisms: 1,3-dipolar cycloaddition, oxygen addition, and single electron transfer. The kinetic calculation indicated that O3 oxidized aqueous halophenols by reacting with halophenolate anions with the reaction rate constants as high as (0.91–3.47) × 1010 M−1 s−1. The number of halogen substituents affected the kO3, cal values of halophenolate anions, which are in the order of 2,4-dihalophenolate anions >4-halophenolate anions > 2,4,6-trihalophenolate anions. During the ozonation of 2,4,6-tribromophenol (246TBP), the toxic products (dimers and brominated benzoquinones) could be synergistically degraded by O3 and HO•. Thus, ozonation is feasible as a strategy to degrade aromatic DBPs.

Ubiquitin proteasomal system is a potential target of the toxic effects of organophosphorus flame retardant triphenyl phosphate

The consumption of the widely used flame retardant Triphenyl phosphate (TPP) is increasing. It is now frequently detected in the environment and also domestically. Although the possibility of dermal exposure to TPP is quite high, little is known about its potential molecular toxicity mechanisms. In this study, we found that TPP caused cytotoxicity on human skin keratinocytes (HaCaT) and significantly inhibited the proliferation and cell migration in a concentration-dependent manner. Additionally, HaCaT cells were sensitive to TPP-induced apoptosis. Reactive oxygen species production was induced with TPP, which increased the protein carbonylation and lipid peroxidation levels. Moreover, TPP inhibited proteasome activity and increased the accumulation of ubiquitinated proteins. Exposure to TPP significantly increased the HSP90, HSP70, GRP94 and GRP78 protein levels. Overall, our findings indicate that TPP may pose a risk to human health and contribute to the current understanding of the risks of TPP at the molecular level.

High content analysis of in vitro alveolar macrophage responses can provide mechanistic insight for inhaled product safety assessment

Assessing the safety of inhaled substances in the alveolar region of the lung requires an understanding of how the respired material interacts with both physical and immunological barriers. Human alveolar-like macrophages in vitro provide a platform to assess the immunological response in the airways and may better inform the understanding of a response to an inhaled challenge being adaptive or adverse. The aim of this study was to determine if a morphometric phenotyping approach could discriminate between different inhaled nicotine products and indicate the potential mechanism of toxicity of a substance. Cigarette smoke (CS) and e-liquids extracted into cell culture medium were applied to human alveolar-like macrophages in mono-culture (ImmuONE™) and co-culture (ImmuLUNG™) to test the hypothesis. Phenotype profiling of cell responses was highly reproducible and clearly distinguished the different responses to CS and e-liquids. Whilst the phenotypes of untreated macrophages were similar regardless of culture condition, macrophages cultured in the presence of epithelial cells were more sensitive to CS-induced changes related to cell size and vacuolation processes. This technique demonstrated phenotypical observations typical for CS exposure and indicative of the established mechanisms of toxicity. The technique provides a rapid screening approach to determine detailed immunological responses in the airways which can be linked to potentially adverse pathways and support inhalation safety assessment.

Daily Variability in Urinary Artificial Sweeteners and Its Association with Oxidative Stress Biomarkers.

Urinary artificial sweeteners (ASs) have been proved to be useful biomarkers for assessing their dietary intakes; however, it is unclear how well a spot urine sample may represent a longer-term exposure. Therefore, a longitudinal study was designed and six ASs and two oxidative stress biomarkers, namely, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA), were determined. Acesulfame (ACE) and saccharin (SAC) were detected in most urines with concentration ranges of <LOQ-33,870 and <LOQ-8100 ng/mL, respectively. Poor intrasubject variability was found in AS measurements, and at least 20 voids were required to estimate participant-specific mean for AS exposures. Furthermore, ASs exhibited significant positive interactions with 8-OHdG and MDA (p < 0.001). A hazard quotient implies safe exposure levels of the participants to ACE and SAC. To the best of our knowledge, this is the first study on the sampling strategy of ASs in urines on a temporal basis, together with exploring their potential toxicity mechanisms.

Wildfire Smoke Exposure during Pregnancy: A Review of Potential Mechanisms of Placental Toxicity, Impact on Obstetric Outcomes, and Strategies to Reduce Exposure.

Climate change is accelerating the intensity and frequency of wildfires globally. Understanding how wildfire smoke (WS) may lead to adverse pregnancy outcomes and alterations in placental function via biological mechanisms is critical to mitigate the harms of exposure. We aim to review the literature surrounding WS, placental biology, biological mechanisms underlying adverse pregnancy outcomes as well as interventions and strategies to avoid WS exposure in pregnancy. This review includes epidemiologic and experimental laboratory-based studies of WS, air pollution, particulate matter (PM), and other chemicals related to combustion in relation to obstetric outcomes and placental biology. We summarized the available clinical, animal, and placental studies with WS and other combustion products such as tobacco, diesel, and wood smoke. Additionally, we reviewed current recommendations for prevention of WS exposure. We found that there is limited data specific to WS; however, studies on air pollution and other combustion sources suggest a link to inflammation, oxidative stress, endocrine disruption, DNA damage, telomere shortening, epigenetic changes, as well as metabolic, vascular, and endothelial dysregulation in the maternal-fetal unit. These alterations in placental biology contribute to adverse obstetric outcomes that disproportionally affect the most vulnerable. Limiting time outdoors, wearing N95 respirator face masks and using high quality indoor air filters during wildfire events reduces exposure to related environmental exposures and may mitigate morbidities attributable to WS.