Potential Mechanisms Of Toxicity Research Articles

Toxic effects of octocrylene on zebrafish larvae and liver cell line (ZFL).

Octocrylene (OC) is a broad-spectrum ultraviolet-absorbing chemical used in sunscreen and other personal care products. Its health effects are a concern because it has been detected in water, fish, humans, and food chains. In vivo and in vitro investigations were performed in zebrafish (Danio rerio) larvae and a zebrafish liver cell line (ZFL), respectively, to understand the potential risks and molecular mechanisms of OC toxicity. The 96-h median lethal concentration (LC50) of OC was determined to be 251.8μM in larvae and 5.5μM in ZFL cells. Quantitative real-time PCR (qRT-PCR) showed that OC induced the expression of genes for CYPs (CYP1A, CYP3A65), estrogen receptors (ERα, ERβ1, GPER), vitellogenin (VTG1), and sex determination (BRCA2, CYP19A, DMRT1, SOX9A), both in vitro and in vivo. A whole-transcriptome sequencing method was used to evaluate the gene expression profile of larvae exposed to OC. OC was found to mediate the biosynthesis of estrogens (such as estriol) and affect the antioxidant pathway (glutathione transferases and peroxisome). These findings clarify the toxic effects and molecular mechanisms of OC and support banning its use in cosmetics.

Carbon dots inhibit root growth by disrupting auxin biosynthesis and transport in Arabidopsis

Carbon dots (CDs) possess considerable potentials in fields like biomarker and cell imaging due to its good fluorescence properties. Nevertheless, the molecular mechanism concerning influences of CDs on plant growth still remains unknown. In this study, the subcellular localization of CDs in Arabidopsis and the molecular mechanism of CDs toxicity to plants were investigated. Results demonstrate that CDs tend to accumulate in meristematic nucleus of root tips. CDs can inhibit growth of meristem zone of primary root (PR) of Arabidopsis seedlings significantly. The transcription level of auxin biosynthesis related genes decreases and the abundance of auxin efflux carriers PIN1 and PIN2 declines after 40 mg/L CDs treatment, thus lowering the auxin level in root tips. Moreover, CDs weaken activity of cell division in meristem zone by disturbing expressions of DNA damage repair genes and cell cycle regulation genes, thus enabling to inhibit growth of the meristem zone. To sum up, CDs inhibit growth of Arabidopsis seedlings through above pathways. These results provide useful information to elaborate potential toxicity mechanism of CDs on terrestrial plants.

FXR activation prevents liver injury induced by Tripterygium wilfordii preparations

Tripterygium glycosides tablets (TGT) and Tripterygium wilfordii tablets (TWT) are the preparations of Tripterygium wilfordii used to treat rheumatoid arthritis (RA) in the clinic, but the hepatotoxicity was reported frequently. This study aimed to determine the potential toxicity mechanism of liver injury induced by the preparations of Tripterygium wilfordii in mice. Here, we performed metabolomic analysis, pathological analysis and biochemical analysis of samples from mice with liver injury induced by TGT and TWT, which revealed that liver injury was associated with bile acid metabolism disorder. Quantitative real-time PCR (QPCR) and western blot indicated that the above changes were accompanied by inhibition of farnesoid X receptor (FXR) signalling. Liver injury from TWT could be alleviated by treatment of the FXR agonist obeticholic acid (OCA) via activation of the FXR to inhibit the c-Jun N-terminal kinase (JNK) pathway and improve bile acid metabolism disorder by activating bile salt export pump (BSEP) and organic solute-transporter-β (OSTB). The data demonstrate that FXR signalling pathway plays a key role in T. wilfordii-induced liver injury, which could be alleviated by activated FXR. These results indicate that FXR activation by OCA may offer a promising therapeutic opportunity against hepatotoxicity from the preparations of T. wilfordii.

Effects of nonylphenol exposure on histological changes, apoptosis and time-course transcriptome in gills of white shrimp Litopenaeus vannamei

Nonylphenol (NP) is considered as one of the persistent organic pollutants (POPs) in the environment. Pacific white shrimp Litopenaeus vannamei is the predominant species in China, which is frequently affected by environmental pollutants. However, potential toxicity mechanism of NP in shrimp has not been comprehensively studied. To explore the physiological changes and molecular mechanism involved in NP exposure of shrimp, we analyzed histological alterations, apoptosis and transcriptional responses of L.vannamei subjected to NP. Results indicated that significant changes in the histoarchitecture of the gills were observed after NP exposure for 3, 12 and 48 h. Apoptosis was also detected in a time-dependent manner. Numerous differentially expressed genes (DEGs) were obtained at 3 h, 12 h and 48 h after exposure. On the basis of the expression patterns over the time course, these DEGs were classified into 12 clusters. GO and KEGG enrichment analysis of these DEGs was carried out and a dynamic and global view was obtained in shrimp after NP exposure on a transcriptome level. In addition, 15 DEGs involved in immune response, apoptosis, DNA repair, osmoregulation etc. were selected for qRT-PCR validation. The expression patterns of these DEGs kept a well consistent with the high-throughput data at different timepoints, which confirmed the accuracy and reliability of the transcriptome data. All the results demonstrated that NP exposure might lead to impairments of biological functions in gills, alter immune and antioxidant response, compromise DNA repair and anti-apoptosis abilities of shrimp, cause severe histopathological changes and eventually trigger apoptosis. The present study enriched the information on the toxicity mechanism of crustaceans in response to NP exposure.

Gene co-expression network analysis reveals mechanisms underlying ozone-induced carbamazepine toxicity in zebrafish (Danio rerio) embryos

Sewage effluent ozonation can reduce concentrations of chemical pollutants including pharmaceutical residues. However, the formation of potentially toxic ozonation byproducts (OBPs) is a matter of concern. This study sought to elucidate toxicity mechanisms of ozonated carbamazepine (CBZ), an anti-epileptic drug frequently detected in sewage effluents and surface water, in zebrafish embryos (Danio rerio). Embryos were exposed to ozonated and non-ozonated CBZ from 3 h post-fertilization (hpf) until 144 hpf. Embryotoxicity endpoints (proportion of dead and malformed embryos) were assessed at 24, 48, and 144 hpf. Heart rate was recorded at 48 hpf. Exposure to ozonated CBZ gave rise to cardiovascular-related malformations and reduced heart rate. Moreover, embryo-larvae exposed to ozonated CBZ displayed a lack of swim bladder inflation. Hence, the expression patterns of CBZ target genes involved in cardiovascular and embryonal development were investigated through a stepwise gene co-expression analysis approach. Two co-expression networks and their upstream transcription regulators were identified, offering mechanistic explanations for the observed toxicity phenotypes. The study presents a novel application of gene co-expression analysis elucidating potential toxicity mechanisms of an ozonated pharmaceutical with environmental relevance. The resulting data was used to establish a putative adverse outcome pathway (AOP).

Identification of Dose-Dependent DNA Damage and Repair Responses From Subchronic Exposure to 1,4-Dioxane in Mice Using a Systems Analysis Approach.

1,4-Dioxane (1,4-DX) is an environmental contaminant found in drinking water throughout the United States. Although it is a suspected liver carcinogen, there is no federal or state maximum contaminant level for 1,4-DX in drinking water. Very little is known about the mechanisms by which this chemical elicits liver carcinogenicity. In the present study, female BDF-1 mice were exposed to 1,4-DX (0, 50, 500, and 5,000mg/L) in their drinking water for 1 or 4 weeks, to explore the toxic effects. Histopathological studies and a multi-omics approach (transcriptomics and metabolomics) were performed to investigate potential mechanisms of toxicity. Immunohistochemical analysis of the liver revealed increased H2AXγ-positive hepatocytes (a marker of DNA double-strand breaks), and an expansion of precholangiocytes (reflecting both DNA damage and repair mechanisms) after exposure. Liver transcriptomics revealed 1,4-DX-induced perturbations in signaling pathways predicted to impact the oxidative stress response, detoxification, and DNA damage. Liver, kidney, feces, and urine metabolomic profiling revealed no effect of 1,4-DX exposure, and bile acid quantification in liver and feces similarly showed no effect of exposure. We speculate that the results may be reflective of DNA damage being counterbalanced by the repair response, with the net result being a null overall effect on the systemic biochemistry of the exposed mice. Our results show a novel approach for the investigation of environmental chemicals that do not elicit cell death but have activated the repair systems in response to 1,4-DX exposure.

DNA Cleavage by Chemically Exfoliated Molybdenum Disulfide Nanosheets.

Chemically exfoliated MoS2 (ce-MoS2) nanosheets have been widely used in biomedical and environmental fields. Some in vitro studies demonstrated that ce-MoS2 might induce toxicity. However, the understanding of the mechanism of potential toxicity is lacking. In this study, we found that ce-MoS2 could directly induce breakage of double-stranded DNA with or without an external energy input, making it different from other two-dimensional nanomaterials. In a dark environment, the DNA cleavage exhibited a pH-dependent trend due to reactive oxygen species generation under different pH values. Under photoirradiation, DNA cleavage could be enhanced. This study provides insights into the potential environmental risk and toxicity of ce-MoS2 in the aquatic environment.

Biosafety risk assessment of nanoparticles: Evidence from food case studies.

Nanotechnology provides a wide range of benefits in the food industry in improving food tastes, textures, sensations, quality, shelf life, and food safety. Recently, potential adverse effects such as toxicity and safety concerns have been associated with the increasing use of engineered nanoparticles in food industry. Additionally, very limited information is known concerning the behavior, properties and effects of food nano-materials in the gastrointestinal tract. There is explores the current advances and provides insights of the potential risks of nanoparticles in the food industry. Specifically, characteristics of food nanoparticles and their absorption in the gastrointestinal tract, the effects of food nanoparticles against the gastrointestinal microflora, and the potential toxicity mechanisms in different organs and body systems are discussed. This review would provide references for further investigation of nano-materials toxicity effect in foods and their molecular mechanisms. It will help to develop safer foods and expand nano-materials applications in safe manner.

DNA methylome signatures as epigenetic biomarkers of hexanal associated with lung toxicity.

BackgroundNumerous studies have investigated the relationship of environmental exposure, epigenetic effects, and human diseases. These linkages may contribute to the potential toxicity mechanisms of environmental chemicals. Here, we investigated the epigenetic pulmonary response of hexanal, a major indoor irritant, following inhalation exposure in F-344 rats.MethodsBased on DNA methylation profiling in gene promoter regions, we identified hexanal-characterized methylated sites and target genes using an unpaired t-test with a fold-change cutoff of ≥ 3.0 and a p-value < 0.05. We also conducted an integrated analysis of DNA methylation and mRNA expression data to identify core anti-correlated target genes of hexanal exposure. To further investigate the potential key biological processes and pathways of core DNA methylated target genes, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed.ResultsThirty-six dose-dependent methylated genes and anti-correlated target genes of DNA methylation and mRNA in lung tissue of hexanal exposed F-344 rats were identified. These genes were involved in diverse biological processes such as neuroactive ligand-receptor interaction, protein kinase cascade, and intracellular signaling cascade associated with pulmonary toxicity. These results suggest that novel DNA methylation-based epigenetic biomarkers of exposure to hexanal and elucidate the potential pulmonary toxicological mechanisms of action of hexanal.

TGFβ2 and TGFβ3 mediate appropriate context-dependent phenotype of rat valvular interstitial cells

SummaryThis study focused on characterizing the potential mechanism of valvular toxicity caused by TGFβ receptor inhibitors (TGFβRis) using rat valvular interstitial cells (VICs) to evaluate early biological responses to TGFβR inhibition. Three TGFβRis that achieved similar exposures in the rat were assessed. Two dual TGFβRI/-RII inhibitors caused valvulopathy, whereas a selective TGFβRI inhibitor did not, leading to a hypothesis that TGFβ receptor selectivity may influence the potency of valvular toxicity. The dual valvular toxic inhibitors had the most profound effect on altering VIC phenotype including altered morphology, migration, and extracellular matrix production. Reduction of TGFβ expression demonstrated that combined TGFβ2/β3 inhibition by small interfering RNA or neutralizing antibodies caused similar alterations as TGFβRis. Inhibition of TGFβ3 transcription was only associated with the dual TGFβRis, suggesting that TGFβRII inhibition impacts TGFβ3 transcriptional regulation, and that the potency of valvular toxicity may relate to alteration of TGFβ2/β3-mediated processes involved in maintaining proper balance of VIC phenotypes in the heart valve.

Molecular Assessment of the Toxic Mechanism of the Latest Neonicotinoid Dinotefuran with Glutathione Peroxidase 6 from Arabidopsis thaliana.

With widespread applications of the latest neonicotinoid in agriculture, dinotefuran has gradually become a hazardous contaminant for plants through the generation of excessive reactive oxygen species. However, the potential toxic mechanisms of oxidative damages to plants induced by dinotefuran are still unknown. As a core component of the glutathione antioxidant enzyme system, glutathione peroxidases have been used as biomarkers to reflect excessive oxidative stress. In this study, the hazardous effects of dinotefuran on AtGPX6 were investigated at the molecular level. The intrinsic fluorescence intensity of AtGPX6 was quenched using the static quenching mechanism upon binding with dinotefuran. Moreover, a single binding site was predicted for AtGPX6 toward dinotefuran, and the complex formation was presumed to be driven by hydrogen bonds or van der Waals forces, which conformed with the molecular docking results. In addition, AtGPX6 exhibited moderate binding affinity with dinotefuran based on the bio-layer interferometry assay. In addition, the loosening and unfolding of the protein skeleton of AtGPX6 with the addition of dinotefuran were explored along with the increase of hydrophobicity around tryptophan residues. Lastly, the toxic effects of dinotefuran on the root growth of Arabidopsis seedlings were also examined. The exploration of the binding mechanism of dinotefuran with AtGPX6 at the molecular level would provide the toxicity assessment of dinotefuran on plants.

Lycopene prevents DEHP-induced testicular endoplasmic reticulum stress via regulating nuclear xenobiotic receptors and unfolded protein response in mice.

Lycopene (LYC) is a potent antioxidant synthesized by red vegetables or plants. Di-2-ethylhexyl phthalate (DEHP) is frequently detected in diverse agricultural environments and considered as a reproductive toxicant. The present research was designed to assess the potential mechanisms of DEHP-induced testicular toxicity and the treatment efficacy of LYC. In this study, after the oral administration of LYC at the dose of 5 mg per kg b.w. per day, mice were given 500 or 1000 mg per kg b.w. per day of DEHP. This research suggested that LYC prevented the DEHP-induced disorder at the levels of activity and content of CYP450 enzymes. LYC attenuated DEHP-caused enhancement in nuclear xenobiotic receptors (NXRs) and the phase I metabolizing enzymes (CYP1, CYP2, CYP3, etc.) levels. Furthermore, endoplasmic reticulum (ER) stress was induced by DEHP and triggered unfolded protein response (UPR). Interestingly, LYC could effectively ameliorate these "hit". The present study suggested that LYC prevents DEHP-induced ER stress in testis via regulating NXRs and UPRER.

Plant and Fungal Hepatotoxicities of Cattle in Australia, with a Focus on Minimally Understood Toxins.

Plant- and fungus-derived hepatotoxins are a major cause of disease and production losses in ruminants in Australia and around the world. Many are well studied and described in the literature; however, this is not the case for a number of hepatotoxicities with economic and animal welfare impacts, such as acute bovine liver disease (ABLD), brassica-associated liver disease (BALD) and Trema tomentosa, Argentipallium blandowskianum and Lythrum hyssopifolia toxicity. Additionally, significant overlap in the clinical presentation and pathology of these conditions can present a diagnostic challenge for veterinarians. This review summarizes the current and most recently published knowledge of common plant- and fungus-associated hepatotoxins affecting cattle in Australia, with a focus on the mechanisms of toxicity and distinguishing diagnostic features. Consolidation of the current understanding of hepatotoxic mechanisms in cattle provides insight into the potential mechanisms of lesser-known toxins, including cellular and subcellular targets and potential metabolic pathways. In the absence of specific etiological investigations, the study of epidemiological, clinical and pathological features of hepatotoxicity provides valuable insights into potential toxic mechanisms and is integral for the successful diagnosis and management of these conditions.

NOD-like receptor signaling pathway activation: A potential mechanism underlying negative effects of benzo(α)pyrene on zebrafish

Benzo(α)pyrene (BaP) is one of typical polycyclic aromatic hydrocarbons (PAHs) in aquatic environments and has been shown to cause toxic effects to aquatic animals. Although the negative effects of BaP have been investigated, the potential toxic mechanisms remain uncharacterized. To explore the potential mechanisms mediating the toxic effects of BaP, zebrafish (Danio rerio) were exposed to BaP for 15 days and the toxic effects of BaP in zebrafish liver were investigated using physiological and transcriptomic analyses. After 15-day BaP exposure, zebrafish liver exhibited abnormalities including increased cytoplasmic vacuolation, inflammatory cell infiltration, swelled nuclei and irregular pigmentation. BaP exposure also induced oxidative stress to the liver of zebrafish. Transcriptomic profiles revealed 5129 differentially expressed genes (DEGs) after 15-days of BaP exposure, and the vast majority of DEGs were up-regulated under BaP treatment. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggest that genes related to immune response were significantly dysregulated. Furthermore, the nucleotide-binding, oligomerization domain (NOD)-like receptor signaling pathway was significantly enriched and most of the genes in this pathway exhibited enhanced expression after BaP exposure. These results partially explained the mechanisms underlying the toxic effects of BaP on zebrafish liver. In conclusion, BaP has the potential to induce physiological responses in zebrafish liver through altering associated genes.

Developmental toxicity of Clerodendrum cyrtophyllum turcz ethanol extract in zebrafish embryo

Ethnopharmacological relevanceClerodendrum cyrtophyllum Turcz has been used in traditional medicine for the treatment of various diseases. In spite of its therapeutic applications, research on its toxicity and teratogenicity is still limited. Aim of the studyThe study aimed to investigate the developmental toxicity of the ethanol extract of C. cyrtophyllum (EE) in zebrafish embryo model. Material and methodsMajor compounds from crude ethanol extract of Clerodendron cyrtophyllum Turcz leaves were determined using HPLC-DAD-Orbitrap-MS analysis. The developmental toxicity of EE were investigated using zebrafish embryo model. Zebrafish embryos at 6 h post-fertilization (hpf) were treated with EE at different concentrations. Egg coagulation, mortality, hatching, yolk sac edema, pericardial edema and teratogenicity were recorded each day for during a 5-day exposure. At time point 120 hpf, body length, pericardial area, heartbeat and yolk sac area were assessed. In order to elucidate molecular mechanisms for the developmental toxicity of EE, we further evaluated the effects of the EE on the expression of genes involved on signaling pathways affecting fish embryo’s development such as heart development (gata5, myl7, myh6, has2, hand2, nkx 2.5), oxidative stress (cat, sod1, gpx4, gstp2), wnt pathway (β-catenin, wnt3a, wnt5, wnt8a, wnt11), or cell apoptosis (p53, bax, bcl2, casp3, casp8, casp9, apaf-1, gadd45bb) using qRT-PCR analysis. ResultsOur results demonstrated that three major components including acteoside, cirsilineol and cirsilineol-4'-O-β-D-glucopyranoside were identified from EE. EE exposure during 6–96 h post-fertilization (hpf) at doses ranging from 80 to 200 μg/mL increased embryo mortality and reduced hatching rate. EE exposure at 20 and 40 μg/mL until 72–120 hpf induced a series of malformations, including yolk sac edema, pericardial edema, spine deformation, shorter body length. Based on two prediction models using a teratogenic index (TI), a 25% lethality concentration (LD25) and the no observed-adverse-effect level (NOAEL), EE is considered as teratogenic for zebrafish embryos with TI (LC50/EC50) and LD25/NOAEC values at 96 hpf reaching 3.87 and 15.73 respectively. The mRNA expression levels of p53, casp8, bax/bcl2, gstp2, nkx2.5, wnt3a, wnt11, gadd45bb and gata5 were significantly upregulated by EE exposure at 20 and 40 μg/mL while the expression of wnt5, hand2 and bcl2 were downregulated. ConclusionsThese results provide evidence for toxicity effects of EE to embryo stages and provide an insight into the potential toxicity mechanisms on embryonic development.

In Vitro and In Vivo Models for Evaluating the Oral Toxicity of Nanomedicines.

Toxicity studies for conventional oral drug formulations are standardized and well documented, as required by the guidelines of administrative agencies such as the US Food & Drug Administration (FDA), the European Medicines Agency (EMA) or European Medicines Evaluation Agency (EMEA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). Researchers tend to extrapolate these standardized protocols to evaluate nanoformulations (NFs) because standard nanotoxicity protocols are still lacking in nonclinical studies for testing orally delivered NFs. However, such strategies have generated many inconsistent results because they do not account for the specific physicochemical properties of nanomedicines. Due to their tiny size, accumulated surface charge and tension, sizeable surface-area-to-volume ratio, and high chemical/structural complexity, orally delivered NFs may generate severe topical toxicities to the gastrointestinal tract and metabolic organs, including the liver and kidney. Such toxicities involve immune responses that reflect different mechanisms than those triggered by conventional formulations. Herein, we briefly analyze the potential oral toxicity mechanisms of NFs and describe recently reported in vitro and in vivo models that attempt to address the specific oral toxicity of nanomedicines. We also discuss approaches that may be used to develop nontoxic NFs for oral drug delivery.

Inhibition in growth and cardiotoxicity of tris (2-butoxyethyl) phosphate through down-regulating Wnt signaling pathway in early developmental stage of zebrafish (Danio rerio)

As a common organophosphorus flame retardant, tris (2-butoxyethyl) phosphate (TBOEP) is detected in water environment and aquatic animals extensively. Despite previous researches have reported the developmental toxicity of TBOEP in zebrafish (Danio rerio) larvae, few research focused on its underlying mechanisms. In this study, zebrafish embryos were exposed to 0, 20, 200, 1000 and 2000 µg/L TBOEP from 2 until 120 h post-fertilization (hpf) to determine potential mechanisms of developmental toxicity of this compound. Early developmental stage parameters such as body length, survival rate, hatching rate and heart rate were decreased, while malformation rate was ascended. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay was carried out at 12, 24, 72 and 120 hpf to demonstrate alterations in expression of genes of Wnt signaling pathway. The results indicated that axin1 was significantly up-regulated, while β-catenin, pkc and wnt11 were down-regulated. Correlation analysis indicated that expression of these genes was significantly correlated with body length. Furthermore, apoptosis was detected in heart region by acridine orange (AO) staining and terminal deoxynucleotide transferase-mediated deoxy-UTP nick end labeling (TUNEL) assay. In addition, at 120 hpf, occurrence of oxidative stress was observed in zebrafish larvae. Moreover, 6-Bromoindirubin-3′-oxime (BIO)， an activator of Wnt pathway, was found to alleviate the inhibiting effects of TBOEP on zebrafish growth. The overall outcomes offered novel viewpoints in toxic effects of TBOEP, and down-regulating Wnt signaling pathway were able to reveal some potential mechanisms of developmental toxicity of TBOEP in zebrafish larvae.

Chronic exposure of hydrogen peroxide alters redox state, apoptosis and endoplasmic reticulum stress in common carp (Cyprinus carpio)

Hydrogen peroxide (H2O2) appears to be ubiquitous in natural water. Higher level of H2O2 can cause physiological stress, immunosuppression and even death in aquatic animals, but the physiological and molecular mechanisms of H2O2 toxicity are not well studied. Thus, the aim of the present study was to exposure potential toxic mechanisms of H2O2 via assessing the effects on redox state, apoptosis and endoplasmic reticulum (ER) stress in common carp. The fish were subjected to four concentrations of H2O2 (0, 0.25, 0.5 and 1 mM) for 14 days. And then, the tissues including blood, liver, muscle, gills, intestines, heart, kidney and spleen were collected to measure biochemical parameter and gene expression. The results showed that H2O2 exposure suppressed the majority antioxidative parameters in serum, liver, muscle and intestines, but enhanced T-SOD, CAT and T-AOC levels in gills. In all tested tissues, the MDA content was significantly promoted by H2O2 exposure. The oxidative stress-related genes including nrf2, gstα, sod, cat and/or gpx1 were upregulated in liver, gills, muscle, intestines, and/or kidney, but downregulated in heart after H2O2 exposure. Moreover, the ho-1 mRNA level was inhibited by H2O2 exposure in all tissues except intestines and spleen. After 14 days of exposure, H2O2 induced ER stress and initiated IRE1 and PERK pathways, which activated downstream genes, including chop, grp78 and/or xbp1s, to regulate UPR in liver, gills, muscle and/or heart. Meanwhile, H2O2 exposure activated MAPK pathway to regulate mitochondria-related genes including bcl-2, bax and cytc, which further triggered cas-8, cas-9 and cas-3, and accelerated apoptosis in liver, gills, muscle and heart. Importantly, in different tissues, the genes associated with oxidative stress, ER stress and apoptosis showed a different influence, and more significant influence was observed in the muscle, gills and liver. Overall results suggested that long-term H2O2 exposure induced oxidative stress, ER stress and apoptosis in the majority of tested tissues of common carp. The Nrf2, IRE1, PERK and MAPK pathways played important roles in H2O2-induced toxicity in fish. These data enriched the toxicity mechanism of H2O2 in fish, which might contribute to the risk assessment of H2O2 in aquatic environment.

Quantitative Digitography Measures Fine Motor Disturbances in Chronically Treated HIV Similar to Parkinson's Disease.

Introduction: Motor and cognitive deficits were compared in aging, chronically treated human immunodeficiency virus (HIV) people, people with mild-to-moderate stage Parkinson’s disease (PD), and healthy controls.Methods: Groups consisted of 36 people with PD, 28 with HIV infection, and 28 healthy controls. Motor function was assessed with the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS-III) and a rapid alternating finger tapping (RAFT) task on an engineered keyboard known as Quantitative Digitography (QDG). Executive function, verbal memory, and visuospatial processing were assessed using standard neuropsychological tests.Results: HIV demonstrated RAFT deficits similar to PD such as reduced amplitude (P = 0.023) and greater amplitude variability (P = 0.019) in the index finger when compared to controls. This fine motor disturbance correlated with HIV’s immune health, measured by their CD4+ T cell count (P < 0.01). The UPDRS did not yield motor differences between HIV and controls. Executive function and verbal memory were impaired in HIV (P = 0.006, P = 0.016, respectively), but not in PD; visuospatial processing was similarly impaired in HIV and PD (P < 0.05) although motor deficits predominated in PD.Conclusions: Fine motor bradykinesia measured quantitatively by QDG RAFT holds promise as a marker of motor decline related to current immune health in aging HIV patients and may be useful in longitudinal studies regarding mechanisms of immunosenescence vs. potential toxicity of combination antiretroviral therapy (cART) in this population. Additionally, motor and cognitive networks in HIV may be affected differently as the disease progresses as observed in the differential patterns of impairment between HIV and PD, providing insight into the mechanisms of brain deterioration in HIV.

Associations between serum concentrations of perfluoroalkyl substances and DNA methylation in women exposed through drinking water: A pilot study in Ronneby, Sweden

BackgroundPerfluoroalkyl substances (PFAS) are widespread synthetic substances with various adverse health effects. A potential mechanism of toxicity for PFAS is via epigenetic changes, such as DNA methylation. However, few studies have evaluated associations between PFAS exposure and DNA methylation among adults, and data is especially scarce for women. Furthermore, exposure to environmental pollutants has been associated with epigenetic age acceleration, but no studies have yet evaluated whether PFAS is associated with epigenetic age acceleration. ObjectivesTo investigate whether exposure to PFAS is associated with alteration of DNA methylation and epigenetic age acceleration among women. MethodsIn this observational pilot study, 59 women (aged 20–47 years at enrollment in 2014) from Ronneby, Sweden, an area with historically high PFAS exposure due to local drinking water contamination, were divided into three PFAS exposure groups (low, medium, and high). Genome-wide methylation of whole-blood DNA was analyzed using the Infinium MethylationEPIC BeadChip. Ingenuity Pathway Analysis was used for in silico functional assessment. Epigenetic age acceleration was derived from the DNA methylation data using Horvath’s epigenetic skin and blood clock. Results117 differentially methylated positions (q < 0.017) and one near-significantly differentially methylated region (S100A13, FWER = 0.020) were identified. In silico functional analyses suggested that genes with altered DNA methylation (q < 0.05) were annotated to cancer, endocrine system disorders, reproductive system disease, as well as pathways such as estrogen receptor signaling, cardiac hypertrophy signaling, PPARα/RXRα activation and telomerase signaling. No differences in epigenetic age acceleration between PFAS exposure groups were noted (p = 0.43). ConclusionThe data suggests that PFAS exposure alters DNA methylation in women highly exposed to PFAS from drinking water. The observed associations should be verified in larger cohorts, and it should also be further investigated whether these changes in methylation also underlie potential phenotypic changes and/or adverse health effects of PFAS.