Zinc ameliorates acrylamide-induced oxidative stress and apoptosis in testicular cells via Nrf2/HO-1/NfkB and Bax/Bcl2 signaling pathway.

BACKGROUND: Acrylamide is a toxic substance formed in some foods that require high-temperature cooking processes and has been implicated as a gonadotoxic agent. Zinc, on the other hand, is a known antioxidant with fertility-enhancing properties. Hence, this study was designed to explore the possible ameliorative effect of zinc in acrylamide-induced gonadotoxicity. METHODS: Twenty-four male Wistar rats were randomized into control, acrylamide (10 mg/kg of acrylamide), acrylamide + 1 mg/kg of zinc, and acrylamide + 3 mg/kg of zinc. The administration was via the oral route and lasted for 56 days. RESULTS: Zinc treatment ameliorated acrylamide-impaired sperm quality, normal testicular histoarchitecture, and hormonal balance, which was accompanied by increased testicular malondialdehyde and interleukin-1ß and decreased testicular superoxide dismutase (SOD) and catalase (CAT). Furthermore, zinc prevented acrylamide-induced downregulation of testicular nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and B-cell lymphoma 2 (BCl2) expression and upregulation of testicular nuclear factor kappa B (NF-κB) and bcl-2-like protein 4 (bax) expression. CONCLUSION: In conclusion, zinc may protect against acrylamide-induced testicular toxicity, mediated by its antioxidant, anti-inflammatory, and antiapoptotic effects.

Dietary and Smoking Acrylamide and Prostate Cancer Risk: CAPLIFE Study.

Acrylamide is a probable carcinogen. Its main sources are the diet and tobacco. The association between acrylamide intake from the diet and tobacco and prostate cancer (PCa) has not been previously evaluated. We aimed to evaluate the relationship between dietary acrylamide intake and exposure to acrylamide through cigarettes and PCa risk. A population-based case-control (CAPLIFE) study was conducted, including 428 incident PCa cases and 393 controls. Smoking and dietary information, with a validated food frequency questionnaire, was collected. We calculated the amount of acrylamide from both sources, and tertiles (Ts) were created. Multivariable logistic regression and restricted cubic spline models were applied to assess the association between exposure to acrylamide and PCa risk. The median was similar for acrylamide in both dietary and smoking acrylamide among PCa cases and controls. No association was observed between dietary acrylamide intake and overall PCa risk (adjusted ORT3vsT1 = 0.90 (95% CI 0.59, 1.37)). A risk trend was observed for acrylamide exposure from cigarette smoking (p-trend = 0.032), with the highest odds in those subjects with the high exposure to acrylamide through cigarettes (adjusted ORT3vsT1 = 1.67 (95% CI 0.92, 3.04)). The restricted cubic splines suggested a linear relationship. In conclusion, acrylamide from smoking could be positively associated with PCa risk, but no association was observed for dietary acrylamide.

Dietary lipoic acid alleviates autism-like behavior induced by acrylamide in adolescent mice: the potential involvement of the gut-brain axis.

Consuming fried foods has been associated with an increased susceptibility to mental health disorders. Nevertheless, the impact of alpha-lipoic acid (α-LA, LA) on fried food-induced autism-like behavior remains unclear. This study aimed to explore how LA affects autism-related behavior and cognitive deficits caused by acrylamide in mice, a representative food hazard found in fried foods. This improvement was accomplished by enhanced synaptic plasticity, increased neurotrophin expression, elevated calcium-binding protein D28k, and restored serotonin. Additionally, LA substantially influenced the abundance of bacteria linked to autism and depression, simultaneously boosted short-chain fatty acid (SCFA) levels in fecal samples, and induced changes in serum amino acid concentrations. In summary, these findings suggested that exposure to acrylamide in adolescent mice could induce the development of social disorders in adulthood. LA showed promise as a nutritional intervention strategy to tackle emotional disorders during adolescence.

Attenuated neuronal differentiation caused by acrylamide is not related to oxidative stress in differentiated human neuroblastoma SH-SY5Y cells.

Acrylamide (ACR) is a known neurotoxicant and developmental neurotoxicant. As a soft electrophile, ACR reacts with thiol groups in cysteine. One hypothesis of ACR induced neurotoxicity and developmental neurotoxicity (DNT) is conjugation with reduced glutathione (GSH) leading to GSH depletion, increased reactive oxygen species (ROS) production and further oxidative stress and cellular damage. In this regard, we have investigated the effect of ACR on neuronal differentiation, glutathione levels and ROS production in the human neuroblastoma SH-SY5Y cell model. After 9 days of differentiation and exposure, ACR significantly impaired area neurites per cell at non-cytotoxic concentrations (0.33 µM and 10 µM). Furthermore, 10 µM ACR dysregulated 9 mRNA markers important for neuronal development, 5 of them being associated with cytoskeleton organization and axonal guidance. At the non-cytotoxic concentrations that significantly attenuate neuronal differentiation, ACR did neither decrease the level of GSH or total glutathione levels, nor increased ROS production. In addition, the expression of 5 mRNA markers for cellular stress was assessed with no significant altered regulation after ACR exposure up to 320 µM. Thus, ACR-induced DNT is not due to GSH depletion and increased ROS production, neither at non-cytotoxic nor cytotoxic concentrations, in the SH-SH5Y model during differentiation.

Metabolomic modelling and neuroprotective effects of carvacrol against acrylamide toxicity in rat's brain and sciatic nerve.

The study aimed to investigate the harmful effects of acrylamide (AA), which forms in carbohydrate-rich foods at temperatures above 120°C, on the central and peripheral nervous systems and to evaluate the potential neuroprotective effects of carvacrol (CRV). Male Wistar Albino rats were subjected to AA (40 mg/kg/bw/day) and CRV (50 mg/kg/bw/day) for 15 days. Following the last administration, evaluations revealed disrupted gait, heightened thermal sensitivity and altered paw withdrawal thresholds in AA-exposed rats. Notably, AA reduced glutathione (GSH) and raised malondialdehyde (MDA) levels in both brain and sciatic nerve tissues. AA raised nuclear factor erythroid 2-related factor 2 (Nrf2), caspase 3 and nuclear factor κB (NF-κB) gene expressions while decreasing NR4A2. CRV co-administration mitigated gait abnormalities, elevated GSH levels and lowered MDA levels in both tissues. CRV also modulated gene expression, reducing Nrf2 and NF-κB while increasing NR4A2. Histopathological signs of AA-induced neurodegeneration and elevated glial fibrillary acidic protein levels observed in brain and sciatic nerve tissues were rectified with simultaneous administration of CRV, thereby demonstrating neuroprotective efficacy in both regions. This study is pioneering in demonstrating CRV's neuroprotective potential against AA-induced neurotoxicity in both central and peripheral nervous systems, effectively addressing limitations in the literature. In conclusion, the study revealed AA-induced neurodegeneration in the brain and sciatic nerve, with CRV significantly mitigating this neurotoxicity. This novel research underscores CRV's promise as a neuroprotective agent against AA-induced adverse effects in both the central and peripheral nervous systems.

Effect of Acrylamide and Mycotoxins in SH-SY5Y Cells: A Review.

Thermal processes induce the formation of undesired toxic components, such as acrylamide (AA), which has been shown to induce brain toxicity in humans and classified as Group 2A by the International Agency of Research in Cancer (IARC), as well as some mycotoxins. AA and mycotoxins' toxicity is studied in several in vitro models, including the neuroblastoma cell line model SH-SY5Y cells. Both AA and mycotoxins occur together in the same food matrix cereal base (bread, pasta, potatoes, coffee roasting, etc.). Therefore, the goal of this review is to deepen the knowledge about the neurological effects that AA and mycotoxins can induce on the in vitro model SH-SY5Y and its mechanism of action (MoA) focusing on the experimental assays reported in publications of the last 10 years. The analysis of the latest publications shows that most of them are focused on cytotoxicity, apoptosis, and alteration in protein expression, while others are interested in oxidative stress, axonopathy, and the disruption of neurite outgrowth. While both AA and mycotoxins have been studied in SH-SY5Y cells separately, the mixture of them is starting to draw the interest of the scientific community. This highlights a new and interesting field to explore due to the findings reported in several publications that can be compared and the implications in human health that both could cause. In relation to the assays used, the most employed were the MTT, axonopathy, and qPCR assays. The concentration dose range studied was 0.1-10 mM for AA and 2 fM to 200 µM depending on the toxicity and time of exposure for mycotoxins. A healthy and varied diet allows the incorporation of a large family of bioactive compounds that can mitigate the toxic effects associated with contaminants present in food. Although this has been reported in some publications for mycotoxins, there is still a big gap for AA which evidences that more investigations are needed to better explore the risks for human health when exposed to AA and mycotoxins.

Toxic encephalopathy, vision loss, and memory disorder caused by acute acrylamide exposure.

Acrylamide (ACR) is an irritant that can cause damage to the eyes, skin, and nervous and reproductive systems. This study aims to illustrate a case of central nervous system and optic nerve damage from exposure to ACR. In this case, a 49-year-old male material handler was accidentally splashed with ACR solution on both of his upper limbs. Consequently, he was admitted to the hospital with toxic encephalopathy, characterized by cerebellar ataxia and slurred speech. Magnetic resonance imaging scan, a brain computed tomography scan blood sample analyses, optic coherence tomography, electroneuromyogram, and visual evoked potentials examination were performed. After 20 days of receiving symptomatic support treatment, the patient continued to experience disturbances in consciousness. Then, he developed vision loss, memory disorders, and symptoms of peripheral neuropathy such as skin peeling, extremity weakness, and absent tendon reflexes. This case report underscores the severe consequences of acute dermal exposure to high concentrations of ACR, resulting in toxic encephalopathy, visual impairment, and memory disorders, which will contribute to a broader understanding of ACR toxicity.

Effect of vinpocetine against acrylamide-induced nephrotoxicity in rats.

Vinpocetine (VIN) is a synthetic drug derived from the natural alkaloid vincamine. The antioxidation and anti-inflammation effects of VIN allow it to be used for multiple therapeutic purposes. So, the research aims to discover the possibility of using VIN to improve the nephrotoxicity of acrylamide (ACR). Twenty-four male albino rats were used in the trial: rats in the control group received 0.5 mL of oral saline, rats in the VIN group received an oral dose of VIN (5 mg/kg), rats in the ACR group received an oral dose of ACR (38.27 mg/kg), and rats in the VIN + ACR group received VIN and then ACR 1 h later. Rat blood and kidneys were collected 10 days after the experiment began to assess biochemical parameters and to examine both renal histopathological and immunohistochemistry. The ACR-treated rats showed high levels of serum kidney function biomarkers (creatinine, urea, and uric acid), serum protein biomarkers (total protein, albumin, and globulin), renal kidney injury molecule (KIM)-1, renal malondialdehyde (MDA), and renal caspase-3 immunoexpression. Moreover, ACR lowed both renal superoxide dismutase (SOD) activity and renal glutathione (GSH) level and caused renal histological alterations. While administration of VIN improved serum kidney function biomarkers, serum protein biomarkers, renal KIM-1, renal oxidative stress biomarkers (MDA, SOD, and GSH), renal caspase-3 immunoexpression, and renal histological alterations induced by ACR. The study confirmed the ability of VIN to reduce the nephrotoxic effects of ACR, which was evident through the results of biochemical parameters and histological and immunohistochemical examinations of the kidney tissues.

Rosmarinic acid mitigates acrylamide induced neurotoxicity via suppressing endoplasmic reticulum stress and inflammation in mouse hippocampus.

BACKGROUND: Acrylamide (ACR) is a widely used compound that is known to be neurotoxic to both experimental animals and humans, causing nerve damage. The widespread presence of ACR in the environment and food means that the toxic risk to human health can no longer be ignored. Rosmarinic acid (RA), a natural polyphenolic compound extracted from the perilla plant, exhibits anti-inflammatory, antioxidant, and other properties. It has also been demon strated to possess promising potential in neuroprotection. However, its role and potential mechanism in treating ACR induced neurotoxicity are still elusive. PURPOSE: This study explores whether RA can improve ACR induced neurotoxicity and its possible mechanism. METHODS: The behavioral method was used to study RA effect on ACR exposed mice's neurological function. We studied its potential mechanism through metabolomics, Nissl staining, HE staining, immunohistochemical analysis, and Western blot. RESULTS: RA pretreatment reversed the increase in mouse landing foot splay and decrease in spontaneous activity caused by 3 weeks of exposure to 50 mg/kg/d ACR. Further experiments demonstrated that RA could prevent ACR induced neuronal apoptosis, significantly downregulate nuclear factor-κB and tumor necrosis factor-α expression, and inhibit NOD-like receptor protein 3 inflammasome activation, thereby reducing inflammation as confirmed by metabolomics results. Additionally, RA treatment prevented endoplasmic reticulum stress (ERS) caused by ACR exposure, as evidenced by the reversal of significant P-IRE1α,TRAF2,CHOP expression increase. CONCLUSION: RA alleviates ACR induced neurotoxicity by inhibiting ERS and inflammation. These results provide a deeper understanding of the mechanism of ACR induced neurotoxicity and propose a potential new treatment method.

Food emulsifiers increase toxicity of food contaminants in three human GI tract cell lines.

Food products simultaneously containing both food contaminants and emulsifiers are common in baked products, coffee and chocolate. Little is known regarding how food contaminants and emulsifiers interact and alter toxicity. Recent studies have shown that while emulsifiers themselves have little toxicity, they could cause changes in the gut microenvironment and lead to issues such as increased uptake of allergens. This study examined toxic effect of two common process contaminants acrylamide (AA) and benzo [a]pyrene (BAP) combined with food emulsifiers polyoxyethylene sorbitan monooleate (TW) or glycerol monostearate (G). In liver cell line HepG2 and gastrointestinal cell lines HIEC6 and Caco-2, toxicities of AA and BAP were increased by TW but not by G as indicated by decrease in IC50 values. Addition of TW also exacerbated gene expression changes caused by AA or BAP. Cellular uptake and cell membrane permeability were enhanced by TW but not by G, but tight junction proteins of Caco-2 monolayer was impacted by both emulsifiers. These results suggested that TW could increase toxicity of AA and BAP through increasing cell permeability thus chemical uptake and potentially through other interactions. The study is to draw the attention of regulators on the potential synergistic interaction of co-occurring chemicals in food.

Dietary exposure to acrylamide among the Malaysian adult population.

This study aimed to estimate the Malaysian adult population's current dietary exposure and margin of exposure (MOE) to the carcinogenic processing contaminant, acrylamide. A total of 448 samples from 11 types of processed foods were collected randomly throughout Malaysia in the year 2015 and 2016. Acrylamide was analysed in samples using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) with a limit of detection (LOD) of 10 µg/kg and a limit of quantification (LOQ) of 25 µg/kg. The highest average level of acrylamide (772 ± 752 µg/kg) was found in potato crisps, followed by French fries (415 ± 914 µg/kg) and biscuits (245 ± 195 µg/kg). The total acrylamide exposure for the adult Malaysian was 0.229 and 1.77 µg/kg body weight per day for average and high consumers, respectively. The MOE were 741 and 1875 for the average consumer based on cancer and non-cancer effects of acrylamide, respectively. Meanwhile, for high consumers, the MOE is 96 for cancer and 243 for non-cancer effects. These findings indicate potential carcinogenic risks from acrylamide exposure among Malaysian adults, especially in Malay and other Bumiputra groups compared to Chinese, Indian, and other ethnic groups, while non-cancer effects appeared less concerning.

Protective effects of vitamin E against acrylamide-induced hepatotoxicity and nephrotoxicity from fetal development to adulthood: Insights into Akt/NF-κB and Bcl-xL/Bax signaling pathways.

Acrylamide (ACR), a toxin present in fried and baked carbohydrate-rich foods, is known to cause liver and kidney damage. This study aimed to investigate the mechanisms of oxidative stress, inflammation, and apoptosis that contribute to liver and kidney damage induced by chronic administration of ACR. Additionally, the effectiveness of vitamin E in mitigating these toxic effects was examined. The study initially involved dividing 40 pregnant rats into four groups. After lactation, the research continued with male offspring rats from each group. The offspring rats were divided into Control, Vitamin E, ACR, and ACR + Vitamin E groups. Following ACR administration, liver and kidney function tests were performed on serum samples. Biochemical analyses, evaluation of inflammation markers, histopathological examination, and assessment of protein levels of Akt/IκBα/NF-κB, Bax, Bcl-xL, and Caspase-9 were conducted on liver and kidney tissues. The analysis demonstrated that ACR adversely affected liver and kidney function, resulting in oxidative stress, increased inflammation, and elevated apoptotic markers. Conversely, administration of vitamin E positively impacted these parameters, restoring them to control levels. Based on the results, the mechanism of ACR's action on oxidative stress and inflammation-induced liver and kidney damage may be associated with the activation of apoptotic markers such as Bax and Caspase-9, as well as the Akt/IκBα/NF-κB signaling pathway. Consequently, the protective properties of vitamin E establish it as an essential vitamin for the prevention or mitigation of various ACR-induced damages.

Adding pulse flours to cereal-based snacks and bakery products: An overview of free asparagine quantification methods and mitigation strategies of acrylamide formation in foods.

Thermal processing techniques can lead to the formation of heat-induced toxic substances. Acrylamide is one contaminant that has received much scientific attention in recent years, and it is formed essentially during the Maillard reaction when foods rich in carbohydrates, particularly reducing sugars (glucose, fructose), and certain free amino acids, especially asparagine (ASN), are processed at high temperatures (>120°C). The highly variable free ASN concentration in raw materials makes it challenging for food businesses to keep acrylamide content below the European Commission benchmark levels, while avoiding flavor, color, and texture impacts on their products. Free ASN concentrations in crops are affected by environment, genotype, and soil fertilization, which can also influence protein content and amino acid composition. This review aims to provide an overview of free ASN and acrylamide quantification methods and mitigation strategies for acrylamide formation in foods, focusing on adding pulse flours to cereal-based snacks and bakery products. Overall, this review emphasizes the importance of these mitigation strategies in minimizing acrylamide formation in plant-based products and ensuring safer and healthier food options.

Chemical and spectroscopic characterization of (Artemisinin/Querctin/ Zinc) novel mixed ligand complex with assessment of its potent high antiviral activity against SARS-CoV-2 and antioxidant capacity against toxicity induced by acrylamide in male rats.

A novel Artemisinin/Quercetin/Zinc (Art/Q/Zn) mixed ligand complex was synthesized, tested for its antiviral activity against coronavirus (SARS-CoV-2), and investigated for its effect against toxicity and oxidative stress induced by acrylamide (Acy), which develops upon cooking starchy foods at high temperatures. The synthesized complex was chemically characterized by performing elemental analysis, conductance measurements, FT-IR, UV, magnetic measurements, and XRD. The morphological surface of the complex Art/Q/Zn was investigated using scanning and transmission electron microscopy (SEM and TEM) and energy dispersive X-ray analysis (XRD). The in vitro antiviral activity of the complex Art/Q/Zn against SARS-CoV-2 and its in vivo activity against Acy-induced toxicity in hepatic and pulmonary tissues were analyzed. An experimental model was used to evaluate the beneficial effects of the novel Art/Q/Zn novel complex on lung and liver toxicities of Acy. Forty male rats were randomly divided into four groups: control, Acy (500 mg/Kg), Art/Q/Zn (30 mg/kg), and a combination of Acy and Art/Q/Zn. The complex was orally administered for 30 days. Hepatic function and inflammation marker (CRP), tumor necrosis factor, interleukin-6 (IL-6), antioxidant enzyme (CAT, SOD, and GPx), marker of oxidative stress (MDA), and blood pressure levels were investigated. Histological and ultrastructure alterations and caspase-3 variations (immunological marker) were also investigated. FT-IR spectra revealed that Zn (II) is able to chelate through C=O and C-OH (Ring II) which are the carbonyl oxygen atoms of the quercetin ligand and carbonyl oxygen atom C=O of the Art ligand, forming Art/Q/Zn complex with the chemical formula [Zn(Q)(Art)(Cl)(H2O)2]⋅3H2O. The novel complex exhibited a potent anti-SARS-CoV-2 activity even at a low concentration (IC50 = 10.14 µg/ml) and was not cytotoxic to the cellular host (CC50 = 208.5 µg/ml). Art/Q/Zn may inhibit the viral replication and binding to the angiotensin-converting enzyme-2 (ACE2) receptor and the main protease inhibitor (MPro), thereby inhibiting the activity of SARS-CoV-2 and this proved by the molecular dynamics simulation. It alleviated Acy hepatic and pulmonary toxicity by improving all biochemical markers. Therefore, it can be concluded that the novel formula Art/Q/Zn complex is an effective antioxidant agent against the oxidative stress series, and it has high inhibitory effect against SARS-CoV-2.

Human coculture model of astrocytes and SH-SY5Y cells to test the neurotoxicity of chemicals.

In this study, we established a coculture model comprising human neuroblastoma SH-SY5Y cells and induced pluripotent stem cell-derived astrocytes, faithfully replicating the human brain environment for in vitro neurotoxicity assessment. We optimized the cell differentiation duration and cell ratios to obtain images conducive to neurite outgrowth evaluation. Subsequently, the neurotoxic effects in the coculture and monoculture of SH-SY5Y cells were confirmed using neurotoxic agents such as acrylamide (ACR) and hydrogen peroxide (H2O2). Disparities in the neurotoxic impacts of ACR and H2O2 within the coculture were mirrored in the expression of genes associated with early neuronal injury. Notably, the reduction in neurite outgrowth induced by neurotoxic agents revealed the coculture's lower sensitivity compared to monocultures. Furthermore, the coculture system exhibited distinct effects of test agents on nerve damage and manifested protective influences on nerve cells. The proposed methodology holds promise for large-scale chemical neurotoxicity screening through neurite change measurements. This in vitro coculture model, accounting for cell interactions, emerges as a valuable tool in toxicity testing, offering insights into the potential effects of chemicals within the human body.

Eugenol alleviates acrylamide-induced rat testicular toxicity by modulating AMPK/p-AKT/mTOR signaling pathway and blood-testis barrier remodeling.

This study aimed to investigate the effects of eugenol treatment on reproductive parameters in acrylamide (ACR)-intoxicated rats. The study evaluated alterations in relative testes and epididymides weights, sperm quality, serum hormonal status, seminal plasma amino acids, testicular cell energy and phospholipids content, oxidative and nitrosative stress parameters, adenosine monophosphate-activated protein kinase/ phosphoinositide 3-kinase/phosphor-protein kinase B/mammalian target of rapamycin (AMPK/PI3K/p-AKT/mTOR) signaling pathway, blood-testis barrier (BTB) remodeling markers, testicular autophagy and apoptotic markers, as well as histopathological alterations in testicular tissues. The results revealed that eugenol treatment demonstrated a significant improvement in sperm quality parameters, with increased sperm cell concentration, progressive motility live sperm, and a reduction in abnormal sperm, compared to the ACR-intoxicated group. Furthermore, eugenol administration increased the levels of seminal plasma amino acids in a dose-dependent manner. In addition, eugenol treatment dose-dependently improved testicular oxidative/nitrosative stress biomarkers by increasing oxidized and reduced glutathione levels and reducing malondialdehyde and nitric oxide contents as compared to ACRgroup. However, eugenol treatment at a high dose restored the expression of AMPK, PI3K, and mTOR genes, to levels comparable to the control group, while significantly increasing p-AKT content compared to the ACRgroup. In conclusion, the obtained findings suggest the potential of eugenol as a therapeutic agent in mitigating ACR-induced detrimental effects on the male reproductive system via amelioration of ROS-mediated autophagy, apoptosis, AMPK/p-AKT/mTOR signaling pathways and BTB remodeling.

Preventive and therapeutic effects of azithromycin on acrylamide-induced neurotoxicity in rats.

BACKGROUND: Acrylamide (ACR) can induce neurotoxicity through different pathways, including oxidative stress and apoptosis. Azithromycin is well-known for its antioxidant and anti-apoptotic properties. OBJECTIVE: To evaluate the potential neuroprotective effect of azithromycin in an in vivo model of ACR-induced neurotoxicity, by investigating its impact on oxidative stress and apoptosis pathways. METHODS: Male rats were divided into eleven groups at random (n = 6). 1:control (vehicle), 2:ACR (50 mg/kg, 11 days, I.P.), 3-7:ACR+ azithromycin (3.1, 6.25, 12.5, 25, 50 mg/kg, 11 days, I.P.), 8-9:ACR+ azithromycin (3.1, 6.25 mg/kg, from day 3-11), 10: ACR+ vitamin E (200 mg/kg, every other day, I.P.), 11. Azithromycin (50 mg/kg). Following the treatment period, a gait score examination was performed, and malondialdehyde (MDA), glutathione (GSH), Bcl-2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2) ratio and caspase-3 levels in the cerebral cortex were measured. RESULTS: Gait abnormality, a drop in GSH, and an increase in lipid peroxidation, Bax/Bcl-2 ratio, and caspase-3 levels were all significantly triggered by ACR in the cerebral cortex versus the control group. Azithromycin 3.1 and 6.25 mg/kg with ACR and azithromycin 6.25 mg/kg with ACR from day 3-11 ameliorated movement disorders caused by ACR. Azithromycin in all doses and both protocols along with ACR decreased the MDA level. Azithromycin (3.1, 6.25 mg/kg) along with ACR in both protocols increased the level of GSH, reduced the Bax/Bcl-2 ratio and caspase-3 amounts in the brain tissue versus the ACR group. CONCLUSIONS: Administration of azithromycin had both preventive and therapeutic effects on ACR-induced neurotoxicity through its antioxidant and antiapoptotic properties.

High-fat diet exacerbated motor dysfunction via necroptosis and neuroinflammation in acrylamide-induced neurotoxicity in mice.

Health risks associated with acrylamide (ACR) or high-fat diet (HFD) exposure alone have been widely concerned in recent years. In a realistic situation, ACR and HFD are generally co-existence, and both are risk factors for the development of neurological diseases. The purpose of the present study was to investigate the combined effects of ACR and HFD on the motor nerve function. As a result, neurobehavioral tests and Nissl staining disclosed that long-term HFD exacerbated motor dysfunction and the damage of spinal cord motor neurons in ACR-exposed mice. Co-exposure of ACR and HFD resulted in morphological changes in neuronal mitochondria of the spinal cord, a significantly reduced mitochondrial subunits NDUFS1, UQCRC2, and MTCO1, released the mitochondrial DNA (mtDNA) into the cytoplasm, and promoted the production of reactive oxygen species (ROS). Combined exposure of HFD and ACR activated the calpain/CDK5/Drp1 axis and caused the mitochondrial excessive division, ultimately increasing MLKL-mediated necroptosis in spinal cord motor neurons. Meanwhile, HFD significantly exacerbated ACR-induced activation of NFkB, NLRP3 inflammasome, and cGAS-STING pathway. Taken together, our findings demonstrated that combined exposure of ACR and HFD aggravated the damage of spinal cord motor neurons via neuroinflammation and necroptosis signaling pathway, pointing to additive effects in mice than the individual stress effects.

Transcriptome analysis of the cerebral cortex of acrylamide-exposed wild-type and IL-1ß-knockout mice.

Acrylamide is an environmental electrophile that has been produced in large amounts for many years. There is concern about the adverse health effects of acrylamide exposure due to its widespread industrial use and also presence in commonly consumed foods and others. IL-1ß is a key cytokine that protects the brain from inflammatory insults, but its role in acrylamide-induced neurotoxicity remains unknown. We reported recently that deletion of IL-1ß gene exacerbates ACR-induced neurotoxicity in mice. The aim of this study was to identify genes or signaling pathway(s) involved in enhancement of ACR-induced neurotoxicity by IL-1ß gene deletion or ACR-induced neurotoxicity to generate a hypothesis mechanism explaining ACR-induced neurotoxicity. C57BL/6 J wild-type and IL-1ß KO mice were exposed to ACR at 0, 12.5, 25 mg/kg by oral gavage for 7 days/week for 4 weeks, followed by extraction of mRNA from mice cerebral cortex for RNA sequence analysis. IL-1ß deletion altered the expression of genes involved in extracellular region, including upregulation of PFN1 gene related to amyotrophic lateral sclerosis and increased the expression of the opposite strand of IL-1ß. Acrylamide exposure enhanced mitochondria oxidative phosphorylation, synapse and ribosome pathways, and activated various pathways of different neurodegenerative diseases, such as Alzheimer disease, Parkinson disease, Huntington disease, and prion disease. Protein network analysis suggested the involvement of different proteins in related to learning and cognitive function, such as Egr1, Egr2, Fos, Nr4a1, and Btg2. Our results identified possible pathways involved in IL-1ß deletion-potentiated and ACR-induced neurotoxicity in mice.

Acrylamide, Applied During Pregnancy and Postpartum Period in Offspring Rats, Significantly Disrupted Myelination by Decreasing the Levels of Myelin-Related Proteins: MBP, MAG, and MOG.

Acrylamide (ACR) is a colorless, odorless, and water-soluble solid molecule. In addition to being an important industrial material, ACR is found in fried and baked carbohydrate-rich foods. ACR is regarded as a typical axonal neurotoxin that induces neuropathy. The brain is protected from oxidative damage by vitamin E, which is regarded as the most powerful fat-soluble antioxidant vitamin. This study aimed to reveal the toxic effect of ACR on the development of myelin in the brain at the molecular level and to examine whether Vitamin E has a neuroprotective effect on the harmful effect of ACR. The study was started by dividing 40 pregnant rats into 4 groups and after lactation, the study was continued with offspring rats (females and males offspring rats) from each group. Offspring rats were equally divided into Control, Vitamin E, ACR, ACR + Vitamin E groups. Following the ACR administration, the Water Maze test was applied to evaluate cognitive function. To evaluate the level of demyelination and remyelination, MBP, MAG, and MOG proteins and mRNA levels were performed. In addition, the degeneration of myelin and glial cells was examined by immunohistochemistry and electron microscopic analysis. Analysis results showed that ACR administration decreased gene and protein levels of myelin-related proteins MBP, MAG, and MOG. The findings were confirmed by histopathological, immunohistochemical, and microscopic examinations. The application of vitamin E improved this negative effect of ACR. It has been observed that ACR may play a role in the pathogenesis of myelin-related neurodegenerative diseases by causing demyelination during gestation, lactation, and post-lactation. In addition, it has been understood that vitamin E supports myelination as a strong neuroprotective vitamin against the toxicity caused by ACR. Our research results suggest that acrylamide may play a role in the etiopathogenesis of demyelinating diseases such as multiple sclerosis in humans since fast-food-type nutrition is very common today and people are chronically exposed to acrylamide.