Subacute Exposure Research Articles

Trajectory of neutrophilic responses in a mouse model of pollutant-aggravated allergic asthma

Experimental studies suggest that neutrophils could contribute to allergic asthma pathogenesis, that is mainly driven by type 2 immunity. Inhalation of diesel exhaust particles (DEP) is implicated in both exacerbation and development of asthma. Since exposure to DEP is associated with a neutrophilic component, we aimed to investigate how exposure to the combination of allergens and DEP modulates neutrophilic responses. Human bronchial epithelial cells (HBEC) were exposed to house dust mite (HDM), DEP or HDM + DEP in vitro to determine the expression of neutrophil-recruiting chemokines. Female (C57BL/6 J) mice were intranasally instilled with saline, DEP, HDM or combined HDM + DEP for 3 weeks (subacute) or 6 weeks (chronic). The neutrophilic responses were determined in lung tissue and bronchoalveolar lavage fluid (BALF). Simultaneous exposure to HDM + DEP resulted in increased CXCL1 and CXCL8 mRNA expression by HBEC in vitro. In mice, subacute exposure to HDM + DEP induced a strong mixed eosinophilic/neutrophilic inflammation in BALF and lung and was associated with higher expression of neutrophil-attracting chemokines and NET formation compared to the sole exposures. After chronic HDM + DEP exposure, a similar neutrophilic response was observed, however the NET formation was less pronounced. Interestingly, the increase of BALF eosinophils was also significantly attenuated after chronic HDM + DEP exposure compared to the subacute exposure. Subacute and chronic HDM + DEP exposure induced goblet cell hyperplasia and airway hyperresponsiveness. Our data suggest a role for neutrophils and NETs in pollutant-aggravated eosinophilic allergic asthma. Moreover, subacute exposure to HDM + DEP induces a mixed eosinophilic/neutrophilic response whereas upon chronic HDM + DEP exposure there is a shift in inflammatory response with a more prominent neutrophilic component.

Effects of antimony exposure on DNA damage and genome-wide variation in zebrafish (Danio rerio) liver

Antimony (Sb) is a potentially toxic and carcinogenic cumulative contaminant that poses a serious threat to aquatic ecosystems. To better clarify the genotoxicity of Sb and its mechanism of action. In this study, we investigated DNA damage and genome-wide variation in the liver of a model organism, zebrafish (Danio rerio), under subacute Sb exposure and explored its potential toxicological mechanisms. The results showed that medium and high concentrations of Sb significantly reduced the total antioxidant capacity and increased the content of reactive oxygen species in zebrafish liver, and further studies revealed that it increased oxidative DNA damage and DNA-DNA cross-link (DDC), but had little effect on DNA-protein cross-link (DPC). The result of resequencing showed that the mutation sites of the genes with high concentrations of Sb were higher than those with medium concentrations, and the mutation was mainly a single nucleotide. The pathways significantly enriched for nonsynonymous single nucleotide polymorphisms (SNPs) and insertion/deletion mutations (InDels) variant genes in the coding regions of both the medium and high Sb-treated groups were ECM-receptor interactions, and the high Sb-treated group also included lysine degradation, hematopoietic cell lineage, and cytokine-cytokine receptor interactions. This suggests that ECM-receptor interactions play an important role in the mechanism of antimony toxicity to the liver of zebrafish.

PGC 1α-Mediates Mitochondrial Damage in the Liver by Inhibiting the Mitochondrial Respiratory Chain as a Non-cholinergic Mechanism of Repeated Low-Level Soman Exposure.

This work aimed to assess whether mitochondrial damage in the liver induced by subacute soman exposure is caused by peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and whether PGC-1α regulates mitochondrial respiratory chain damage. Toxicity mechanism research may provide theoretical support for developing anti-toxic drugs in the future. First, a soman animal model was established in male Sprague-Dawley (SD) rats by subcutaneous soman injection. Then, liver damage was biochemically evaluated, and acetylcholinesterase (AChE) activity was also determined. Transmission electron microscopy (TEM) was performed to examine liver mitochondrial damage, and high-resolution respirometry was carried out for assessing mitochondrial respiration function. In addition, complex I-IV levels were quantitatively evaluated in isolated liver mitochondria by enzyme-linked immunosorbent assay (ELISA). PGC-1α levels were detected with a Jess capillary-based immunoassay device. Finally, oxidative stress was analyzed by quantifying superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), oxidized glutathione (GSSG), and reactive oxygen species (ROS) levels. Repeated low-level soman exposure did not alter AChE activity, while increasing morphological damage of liver mitochondria and liver enzyme levels in rat homogenates. Complex I, II and I + II activities were 2.33, 4.95, and 5.22 times lower after treatment compared with the control group, respectively. Among complexes I-IV, I-III decreased significantly (p < 0.05), and PGC-1α levels were 1.82 times lower after soman exposure than in the control group. Subacute soman exposure significantly increased mitochondrial ROS production, which may cause oxidate stress. These findings indicated dysregulated mitochondrial energy metabolism involves PGC-1α protein expression imbalance, revealing non-cholinergic mechanisms for soman toxicity.

Impact of acute and sub-acute exposure of magnesium oxide nanoparticles on mrigal Cirrhinusmrigala

This experiment was conducted to investigate the impact of acute and sub-acute exposure of magnesium oxide nanoparticles on Mrigal Cirrhinus mrigala. For sub-acute tests 1/100,1/50,1/10 were selected based on the LC50 at 96 h s. Protein, carbohydrate, and lipid, Aspartate aminotransferase, alanine transaminase, lactate dehydrogenase and DPPH, HRSA assays were analyzed in the gill, muscle, and liver of Mrigal. Protein and lipid levels increased on the 7th,14th day compared to control. Carbohydrate levels decreased on the 7th,14th day of exposure, and the enzymatical changes increased on the 7th,14th day. Antioxidant levels highly increased in DPPH assay compared to the HRSA assay. This study provides the biochemical, antioxidant, and behavioral changes in relation to the exposure of MgO NPs.

Role of macrophage AHR/TLR4/STAT3 signaling axis in the colitis induced by non-canonical AHR ligand aflatoxin B1

Here we report that macrophage AHR/TLR/STAT signaling axis is implicated in the colon colitis induced by non-canonical AHR ligand aflatoxin B1 (AFB1). In BALB/c mice gavaged with 5, 25 and 50 µg/kg body weight/day AFB1, we observed severe colitis featured by over-recruitment of myeloid lineage immune cells such as monocytes/macrophage in colon lamina propria. Stressed and damaged colon epithelial cells were observed in low-dose group, while twisted and shortened intestinal crypts being found in middle dose group. Severe tissue damage was induced in the high-dose group. Dose-dependent increases of ROS, NO, and decrease of mitochondrial ROS-suppressor STAT3 were observed in the exposure groups. Further investigation in AFB1-treated human macrophage model found: (1) functional adaptations such as elevation of TNF-alpha and IL-6 secretion, stimulation of phagocytosis, elevation of LTE4 level; (2) overall inflammatory status confirmed by RNA-sequence analysis, in line with up-regulation of immune functional proteins such as ICAM-1, IDO-1, NF-kB-p65, NLRP3, COX-2 and iNOS; (3) mRNA disruption of mitochondrial oxidative phosphorylation complex I units and STATs; (4) perturbation of AHR/TLR/STAT3 signaling axis, including elevated AHR, TLR2, TLR4, and decreased STAT3, p-STAT3 Ser727. Mechanism investigation revealed regulatory links of ligand-dependent AHR/TLR4/STAT3. AHR-TLR4 together regulate MyD88, and STAT3 may be directly regulated by MyD88 (TLR4 downstream molecule) upon AHR/TLR4 binding with ligands. Solely protein level changes of AHR/TLR4 cannot regulate STAT3. Our study suggests that macrophage AHR/TLR4/STAT3 is involved with the colitis induced by sub-acute exposure to AFB1. Future follow-up study will focus on the intervention of the colitis using AHR-anti-inflammatory ligands.

Evaluation of therapeutic effects of aqueous cinnamon extract against obesity associated dysregulation of pituitary-adrenal axis

Obesity is distinguished by unwanted and surplus accumulation of lipids in body principally in adipocytes. Inactive lifestyle and dietary irregularities are considered as premiers among a variety of obesogenic risk factors. Obesity is associated with variations in the concentration of trophic and tropic hormones from pituitary gland affecting different body parts and other endocrine glands including adrenal gland. Current study was design to explore the anti-obesity potential of cinnamon (Cinnamomum verum) against high sugar and high fat induced hyper-activity of pituitary-adrenal (PA) axis and obesity. Twenty-five healthy Wistar albino female rats were selected as model animal. Body weight, oral glucose tolerance test, serum cortisol, hematology and histopathological analysis were performed. The high sugar and high fat induced increase in body eight was decline by cinnamon administration. Hematological analysis revealed a significant decreased concentration of RBCs and hemoglobin and increased WBCs and platelet count following sub-acute exposure of high sugar and high fat changes were attenuated by cinnamon. High sugar and fat associated elevated serum cortisol was normalized after cinnamon exposure. Moreover, cinnamon protected the histopathological alterations following high sugar and fat administration, showed protective effects of Cinnamon against obesity associated dysregulation of PA axis and metabolic impairment.

Subacute Exposure to Low Pb Doses Promotes Oxidative Stress in the Kidneys and Copper Disturbances in the Liver of Male Rats.

Recent data indicate that lead (Pb) can induce adverse effects even at low exposure levels. Moreover, the corresponding mechanisms of low Pb toxicity have not been well identified. In the liver and the kidneys, Pb was found to induce various toxic mechanisms leading to organ physiological disruption. Therefore, the purpose of the study was to simulate low-dose Pb exposure in an animal model with the aim of assessing oxidative status and essential element levels as the main mechanism of Pb toxicity in the liver and kidneys. Furthermore, dose-response modelling was performed in order to determine the benchmark dose (BMD). Forty-two male Wistar rats were divided into seven groups: one control group, and six groups treated for 28 days with 0.1, 0.5, 1, 3, 7, and 15 mg Pb/kg b.w./day, respectively. Oxidative status parameters (superoxide dismutase activity (SOD), superoxide anion radical (O2-), malondialdehyde (MDA), total sulfhydryl groups (SHG), and advanced oxidation protein products (AOPP)) and Pb, copper (Cu), zinc (Zn), manganese (Mn), and iron (Fe) levels were measured. Lowering Cu levels (BMD: 2.7 ng/kg b.w./day), raising AOPP levels (BMD: 0.25 µg/kg b.w./day) in the liver, and inhibiting SOD (BMD: 1.3 ng/kg b.w./day) in the kidneys appear to be the main mechanisms of Pb toxicity. The lowest BMD was derived for a decrease in Cu levels in liver, indicating that this effect is the most sensitive.

The Effects of Diflubenzuron on Acetylcholinesterase (EC 3.1.1.7) Activity and Liver Ultrastructure in Wistar Rats

Diflubenzuron is a commonly used larvicide/biocidal substance. The present study aimed to reveal the effects of diflubenzuron on Acetylcholinesterase (AChE) enzymatic activity and liver histopathology of a mammalian species (rats). The animals fed with various doses of diflubenzuron and the liver tissues of rats were taken on the 10th, 20th, 25th, 45th days and sixth month. AChE activity of liver was measured by spectrophotometer. Tissues were embedded in Araldite 502 (Sigma), took ultrathin sections, and examined under a 100 CX II Transmission Electron Microscope. AChE activity in the chronic dose of diflubenzuron group was like that in the control group. The enzymatic activity in the subacute dose was found to be significantly different from the control group. After subacute dose exposure was terminated, the AChE activity was still lower on the 45th day compared with the control group. Chronic and subacute doses caused adverse effects to liver tissues, such as numerous mitochondria, abnormally structured nuclei in the hepatocytes and many lipid droplets in the sinusoids of the liver ultrastructure. After the subacute dose was terminated, liver damage was still observed on the 20th and 25th days, but the liver tissue was partly regenerated on the 45th day. Cellular damage might recover after 45 days, but AChE activity probably takes more time to reach a normal level.

Effects of PM2.5 Exposure on the ACE/ACE2 Pathway: Possible Implication in COVID-19 Pandemic.

Particulate matter (PM) is a harmful component of urban air pollution and PM2.5, in particular, can settle in the deep airways. The RAS system plays a crucial role in the pathogenesis of pollution-induced inflammatory diseases: the ACE/AngII/AT1 axis activates a pro-inflammatory pathway counteracted by the ACE2/Ang(1-7)/MAS axis, which in turn triggers an anti-inflammatory and protective pathway. However, ACE2 acts also as a receptor through which SARS-CoV-2 penetrates host cells to replicate. COX-2, HO-1, and iNOS are other crucial proteins involved in ultrafine particles (UFP)-induced inflammation and oxidative stress, but closely related to the course of the COVID-19 disease. BALB/c male mice were subjected to PM2.5 sub-acute exposure to study its effects on ACE2 and ACE, COX-2, HO-1 and iNOS proteins levels, in the main organs concerned with the pathogenesis of COVID-19. The results obtained show that sub-acute exposure to PM2.5 induces organ-specific modifications which might predispose to greater susceptibility to severe symptomatology in the case of SARS-CoV-2 infection. The novelty of this work consists in using a molecular study, carried out in the lung but also in the main organs involved in the disease, to analyze the close relationship between exposure to pollution and the pathogenesis of COVID-19.

Ameliorative Effects of Alpha Lipoic Acid, Quercetin and Ascorbic Acid Against Zinc Oxide Nanoparticles Induced Hepatic Damage: In Vivo

The current study envisioned to evaluate time related protective effect of quercetin, alpha lipoic acid and ascorbic acid on liver of mice against sub-acute exposure of zinc oxide (ZnO-NP) nanoparticle. Male Swiss albino mice (n=72) were randomly divided into eight groups (n=9, each group). G1 received saline solution 0.9%; G2 received quercetin (100 mg/kg b.w); G3 received alpha lipoic acid (100 mg/kg b.w); G4 received ascorbic acid (100 mg/kg b.w); G5 received ZnO-NPs (50 mg/kg b.w); G6 received ZnO-NPs with quercetin; G7 received ZnO-NPs with Alpha lipoic acid and G8 co-treated with ZnO-NPs and ascorbic acid for 21 consecutive days. Body weight, hepatosomatic index and plasma biochemical parameters (total protein, albumin, globulin, total cholesterol, triglycerides, high density lipoproteins, low density lipoprotein, aspartate aminotransferase, alanine transaminase, alkaline phosphatase &amp; bilirubin) were estimated. ZnO showed significant increase in body weight and cause alterations in all biochemical parameters. Co-administration of quercetin (100 mg/kg b.w), alpha lipoic acid and ascorbic acid daily along with ZnO-NPs, significantly ameliorate the dramatic alteration in biochemical parameters and hepatocellular necrosis caused by ZnO nanoparticles. Brine shrimp larvae cytotoxicity assay of ZnO nanoparticles showed 0% mortality. Present study concluded that all three active ingredients showed hepatoprotective effects against nanoparticles induced time dependent toxicity.

Lambda cyhalothrin and chlorantraniliprole caused biochemical, histological, and immunohistochemical alterations in male rabbit liver: Ameliorative effect of vitamins A, D, E, C mixture

Pesticides can cause serious environmental and human health consequences such as metabolic disruption and even cancers. Preventive molecules such as vitamins can be an effective solution. The present study aimed to investigate the toxic effect of an insecticide mixture formulation of lambda cyhalothrin and chlorantraniliprole (Ampligo® 150 ZC), on the liver of male rabbits (Oryctolagus cuniculus) and the possible ameliorative effect of vitamins A, D3, E, and C mixture. For that, 18 male rabbits were divided into 3 equal groups: Control (distilled water), AP (20 mg/Kg bw of the insecticide mixture every other day, orally for 28 days), AP+ADEC (20 mg/Kg bw of the insecticide mixture + 0,5 ml of vitamin AD3E+ 200 mg/kg bw of vitamin C every other day). The effects were evaluated on body weight, food intake changes, biochemical parameters, liver histology, and immunohistochemical expression of AFP, Bcl2, E-cadherin, Ki67, and P53. Results indicated that AP reduced weight gain (6.71%) and feed intake, increased ALT, ALP, and TC plasma levels, and caused hepatic tissular damages such as dilatation and congestion of the central vein, sinusoidal dilatation, inflammatory cells infiltration, and collagen deposition. Hepatic immunostaining showed an increase in the tissular expression of AFP, Bcl2, Ki67, and P53 and a significant (p < 0,05) decrease in E-cadherin expression. In contrast, supplementation of vitamins A, D3, E, and C mixture improved the previous observed alterations. Our study revealed that a sub-acute exposure to an insecticide mixture of lambda cyhalothrin and chlorantraniliprole induced numerous functional and structural disorders in the rabbit liver and the addition of vitamins ameliorated these damages.

STRESS RELATED HISTOPATHOLOGICAL CHANGES IN THE HEPATOPANCREAS OF BOTH THE SEXES OF PALAEMONID PRAWN MACROBRACHIUM DAYANUM (HENDERSON) (CRUSTACEA : DECAPODA)

The palaemonid prawns Macrobrachium dayanum(Crustacea: Decapoda) are importantspecies found in river Gomti and are very good bioindicators. These prawns are ideal animals tostudy the histopathological impairments caused by the effect of heavy metals prominent in riverGomti. The test animals were exposed to LC50value (0.15 mg/l and 0.16 mg/l respectively)at acuteexposure for 24, 48,72 and 96h and at subacute exposure25% of 96hr LC50 values of CdCl2 for malesand females (0.0375mg/l &amp; 0.04 mg/l) respectively for 10, 20 and 30 day exposure. Thehistopathological changes were studied in both the sexes in the animals.Marked histopathologicalchanges were noticed in hepatopancreas of M.dayanum after cadmium chloride exposure. At 96 hacute exposure, hepatopancreas showed vacuolization in epithelial cells, necrosis in tunica propria,increased number of migratory cells, granuloma in intertubular connective tissue alongwithkaryorrhexis and karyolysis in cells. Necrotic and degenerative changes in hepatopancreaticepithelium, which were mainly, noticed in R and B cells. Loss of histological architecture along withthe heavy influx of haemocytes was recorded at this stage. After sub-acute exposure large vacuoles,particularly R and B cells were observed along with hypertrophy, necrosis and degenerative changesat most of the places in hepatopancreatic epithelium. Karyorrhexis and pyknosis were common.Increased number of migratory cells in intertubular spaces was a peculiar feature at this stage. Almostcomplete loss of the architecture of hepatopancreas was noticed and about 90 % of thehepatopancreatic tubules were found non–fuctional. The histopathological alteration in males wasmore pronounced than in females, both at acute and sub-acute exposure.

Arctic Stress: Mechanisms and Experimental Models

Humans stay in the Polar regions results in the development of stress caused by a combination of factors such as low air temperature, hypodynamia, hypoxia, and disruption of the daylight cycle. All this strongly indicates the increased requirements for health protection and prevention of morbidity in the population of the Arctic. The problem is topical of search for optimal biological models of Arctic stress intended for preclinical testing of pharmacological and dietary correction of its consequences. Aim analysis of literature data on the pathophysiological mechanisms of polar stress, existing methods for its modeling in the experiment, informative biomarkers and prospects for dietary correction. Selection by keywords and analysis of literary sources using PubMed, Web of Science and Scopus online resources for the period, mainly, 20102022. The reaction to adverse environmental conditions in the Arctic is based on universal mechanisms associated with the excitation of midbrain centers (primarily the hypothalamus) with the development of a subsequent hormonal response from peptide hormones, corticosteroids, catecholamines, and thyroid hormones. The secondary targets of these effects are muscle tissue, endothelium, white and brown adipose tissue, cells of the immune system, in which changes occur aimed at neutralizing external adverse effects. A number of laboratory animal models have been developed to reproduce conditions associated with polar stress, including various types of acute, subacute and chronic cold exposure, as well as its combination with forced physical activity and additional stress factors. Sensitive biomarkers that allow monitoring the severity of polar stress are, firstly, the content of corticosteroids, catecholamines, neuropeptides, micro-RNA (miR-210) in blood plasma, organs and compartments of the brain, expression levels of uncoupling proteins (UCP) in brown adipose tissue, indicators of oxidative stress (lipoperoxide and malondialdehyde content, activity of antioxidant defense enzymes GPX, GR, SOD, catalase and others), levels of bioantioxidants (vitamin E, ascorbic acid, carotenoids, GSH), cytokines and chemokines, including IL-1, IL-6, IL-10, IL-17, IL-33, RANTES, FGF21 and various forms of their receptors, gene expression of signaling molecules (proteinkinases). In the issue of dietary correction of disorders caused by polar stress, the main place is given to the use of dietary antioxidant factors (vitamins E and C, selenium, zinc, coenzyme Q10, cinnamic acids and bioflavonoids). The data available in the world literature form the basis for further study of the molecular mechanisms of polar stress and pathogenetically substantiated methods of its dietary correction.

Toxic effect of cigarette butts leachates on blood markers of Periophthalmus waltoni species from the Persian Gulf region

Cigarette butts (CBs) are one of the most common, long-lasting, and toxic forms of marine and coastal area debris. Although the significance of CBs and the toxic contents of this waste items are well recognized, but there is still a lack of information about the effects of this waste on the aquatic organisms. Therefore in this study, the in-vivo toxic effects of various CBs leachates (smoked cigarette butts with tobacco [SCBs], smoked CBs without tobacco [SFs], and unsmoked filters [USFs]) on cellular and chemical hematologic markers in fish (Periophthalmus waltoni) were evaluated. In three acute, sub-acute, and sub-chronic exposure measurements, P. waltoni exposed to different CBs leachates showed a significant increase in white blood cells, creatine kinase, lactate dehydrogenase, alkaline phosphatase, alanine transaminase, and aspartate transaminase, as well as a decrease in hemoglobin (Hb) levels. The mean ± SD values of Hb in P. waltoni species exposed to different CBs leachates (control, SCBs, SFs and USFs) in acute (1 day) phase were 7.15 ± 0.34, 6.02 ± 0.29, 6.25 ± 0.25 and 6.89 ± 0.1 g/dl respectively. These values in subacute (28 days) phase were 6.70 ± 0.15, 5.19 ± 0.24, 5.67 ± 0.30 and 6.10 ± 0.24 g/dl and in sub chronic exposure (42 days) phase were 7.20 ± 0.40, 5.16 ± 0.30, 5.88 ± 0.34 and 6.60 ± 0.33 g/dl respectively. Our results showed that CBs leachates act as a stressor, leading to changes in some hematologic markers in P. waltoni species. Because of the continued deposition of CBs waste into global aquatic environments, policies to mitigate this waste in coastal areas are needed to prevent potentially negative effects on fish and other aquatic organisms.

Derivation of benchmark doses for male reproductive toxicity in a subacute low-level Pb exposure model in rats

The objectives of the study were to simulate low-level Pb exposure scenario in an animal model and to examine reproductive adverse effects. Based on obtained data, we have performed Benchmark dose (BMD)-response modelling. Male Wistar rats were randomized in seven groups (n = 6): one control and six treated with: 0.1, 0.5, 1, 3, 7, and 15 mg Pb/kg body weight, daily for 28 days by oral gavage. The rats were sacrificed and the blood and testes were used for further analysis of testosterone levels in serum, testicular essential metal levels and histological analysis. The Pb treatment led to a dose-dependent decrease of serum testosterone levels with a negative trend (BMDI 0.17–6.13 mg Pb/kg). Increase of Zn (dose-dependent, BMDI 0.004–19.7 mg Pb/kg) and Cu and a decrease of Mn testicular levels were also detected with unscathed histology of the testes. The presented results might be used in further evaluation of the point of departure in human health risk assessment for Pb.

Acute manganese exposure impairs glutamatergic function in a young mouse model of Alzheimer’s disease

Manganese (Mn) is an essential metal that serves as a cofactor for metalloenzymes important in moderating oxidative stress and the glutamate/glutamine cycle. Mn is typically obtained through the diet, but toxic overexposure can occur through other environmental or occupational exposure routes such as inhalation. Mn is known to accumulate in the brain following exposure and may contribute to the etiology of neurodegenerative disorders such as Alzheimer’s disease (AD) even in the absence of acute neurotoxicity. In the present study, we used in vitro primary cell culture, ex vivo slice electrophysiology and in vivo behavioral approaches to determine if Mn-induced changes in glutamatergic signaling may be altered by genetic risk factors for AD neuropathology. Primary cortical astrocytes incubated with Mn exhibited early rapid clearance of glutamate compared to saline treated astrocytes but decreased clearance over longer time periods, with no effect of the AD genotype. Further, we found that in vivo exposure to a subcutaneous subacute, high dose of Mn as manganese chloride tetrahydrate (3 ×50 mg/kg MnCl2·4(H2O) over 7 days) resulted in increased expression of cortical GLAST protein regardless of genotype, with no changes in GLT-1. Hippocampal long-term potentiation was not altered in APP/PSEN1 mice at this age and neither was it disrupted following Mn exposure. Mn exposure did increase sensitivity to seizure onset following treatment with the excitatory agonist kainic acid, with differing responses between APP/PSEN1 and control mice. These results highlight the sensitivity of the glutamatergic system to Mn exposure. Experiments were performed in young adult APP/PSEN1 mice, prior to cognitive decline or accumulation of hallmark amyloid plaque pathology and following subacute exposure to Mn. The data support a role of Mn in pathophysiology of AD in early stages of the disease and support the need to better understand neurological consequences of Mn exposure in vulnerable populations.

PS-B10-6: CAPILLARY-TO-ARTERIOLAR SIGNALLING, INFLAMMATION AND SMALL VESSEL DISEASE OF THE BRAIN

Objective: Chronic cerebral inflammation is thought to be a mechanism by which hypertension causes small vessel disease of the brain, leading to dementia. Mouse studies have demonstrated enhanced small resistance artery constriction and neurovascular uncoupling in hypertension. We wished to examine whether acute exposure to the predominant inflammatory driver in hypertension, interleukin-1β; (IL-1β;) could account for this dual vascular deficit. Design and method: Pressure myography of freshly isolated mouse posterior cerebellar pial arteries was used to assess contributions of the inwardly rectifying K+ 2.1 (KIR2.1) channel to vasodilation. In order to assess neurovascular coupling from a vascular perspective, we adopted a recently described approach: the Capillary to Parenchymal Arteriole (CaPA) preparation. In the CaPA preparation, penetrating arterioles (&lt; 40ums) with attached capillary branches are isolated and pressurised. The capillary branch and arteriole are independently stimulated via a micropipette and arteriole diameter is recorded. This approach enables the retrograde hyperpolarising signal from the KIR2.1 channel, which propagates against the flow of blood in the brain, to be assessed both in terms of the extent of arteriole vasodilation and the speed of communication (video). In order to assess the effects of perivascular inflammation on cerebrovascular function, we incubated (in culture medium) small pial arteries with IL-1β; for 24 hours prior to study on a pressure myograph rig. KIR2.1 function was assessed using 10 mM exogenous K+. Cerebral arterioles with attached capillaries were incubated with IL-1β; for 2 hours prior to CaPA study. We then examined the capillary-to-arteriolar signalling mechanism via application of 10 mM K+ to the capillary. We also assessed arteriolar tone and reaction to directly applied K+, NS309 and U46619. Results: Preliminary data suggests that sub-acute incubation with exogenous IL-1β; had no effects on the degree of pressure induced constriction of either the pial artery or the arteriole. CaPA preparation showed that the KIR2.1 capillary-to-arteriolar signalling was preserved as well as arteriolar responses to direct K+, NS309 and U46619 following IL-1β; exposure. Conclusions: Whilst chronic cerebral inflammation in the setting of hypertension results in cerebrovascular deficits, sub-acute exposure with IL-1β; does not appear to significantly impair cerebral microvascular function. Precisely how chronic exposure to inflammation in hypertension induces neurovascular uncoupling is the subject of ongoing investigation.

Kadmiyuma Maruz Bırakılan Farelerin Oksidatif Stres Parametreleri ve Kan Lipid Profili üzerinde Resveratrolun Dokuya Özgü İyileştirici Etkisi

Cadmium can cause oxidative damage in organisms through overproduction of free radicals and suppression of the antioxidant defense system. Resveratrol is known as a nutraceutical with antioxidant properties accepted to have protective effects to the toxicity of heavy metals. In this study, we investigated if resveratrol could overwhelm the toxic effect of sub-acute cadmium exposure. Animals were divided to the following groups: 1) Control, 2) Vehicle control, 3) Cadmium (Cd), 4) Resveratrol (Res), 5) Exposure to both Cd and Res (Cd+Res). Increased lipid peroxidation and total sialic acids were determined in testis and lung tissues of mice exposed to Cd with the decreased in paraoxonase (PON1) level and GSH amount. Interestingly, we also found an increased lipid peroxidation and NO levels in lung tissue of mice exposed to Res and Cd + Res, but not in testis tissue. Moreover, increased triglycerides, total cholesterol, very low-density lipoproteins, and low-density lipoproteins as well as reduced high-density lipoproteins were found in mice exposed to Cd and Cd + Res compared to controls. Our results revealed that cadmium induces oxidative damage in tissues, via increased lipid peroxidation, total sialic acids and decreased antioxidant levels as well as disturbs lipid profile. Moreover, our findings indicate that resveratrol may act as “ameliorative” factor against the cadmium exposure in only testis tissue. Thus, we may suggest that ameliorative effect of resveratrol may vary depending on the exposure dose, exposure duration and exposed tissues of animals to the heavy metals.

Neurotoxicity of Chlorpyrifos, Carbofuran, and Cypermethrin in Adolescent Rats’ Brain

Chronic exposure to insecticides, even at low levels, has led to chronic neurotoxicity. Adolescent brain is still undergoing important developments, including in the hippocampus. This study investigated neurotoxicity effects of subacute exposure to chlorpyrifos, carbofuran and cypermethrin in the brain of adolescent rats. This study was performed at the Histology, Biochemistry, and Animal House Laboratory of Jember University from November to December 2021. Subjects were divided into five groups: normal, control, chlorpyrifos, carbofuran, and cypermethrin. Short-term memory was evaluated by Y maze test and tissue damage was evaluated by histological examination. Brain MDA levels were determined by thiobarbituric acid reactive substance method to evaluate the oxidative stress effect on the organ. This study showed spontaneous alternation in the Y maze test and the number of pyramidal neurons in hippocampus decreased in the cypermethrin group. There was a significant elevation of brain MDA level in carbofuran and cypermethrin groups. Thus, cypermethrin causes more severe neurotoxicity than carbofuran and chlorpyrifos. Improvements in the insecticide application management are urgently needed to prevent neurotoxicity.

Subacute exposure to dimethoate induces hepatotoxic and nephrotoxic effects on male rats: Ameliorative effects of ferulic acid

Dimethoate commonly used as environmental ares for control pests which is widely used throughout in the world and itcaused toxic effects on nontarget organisms especially mammalian. Ferulic acid is known to protective compound generally used in toxicology studies. Thus, inthis study, we investigatedthe protective role of ferulic acid against the possible toxic effects of low and high doses of dimethoate. Male rats were randomly divided into six groups: control; ferulic acid; low and high dose dimethoate; both ferulic acid and low dose dimethoate; both ferulic acid and high dose dimethoate. The dimethoate treatment to rats caused oxidative stress in liver and kidney tissue via increased malondialdehyde levels and changes in superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase activities. All dose dimethoate treatments also caused histopathological alterations and differences in activities in alanine aminotransferase, aspartate aminotransferase, total protein, albumin, lactate dehydrogenase, total cholesterol, urea, uric acid, and creatinine levels. The histopathological results verified the biochemical findings for both liver and kidney. Co-administration of ferulic acid with dimethoate improved antioxidative parameters and eased some biochemical parameters mentioned above. Ferulic acid was also seen to play a beneficial role in the histopathological effects of dimethoate for both liver and kidney.