-
International Journal of Molecular... Mar 2021Acrylamide is a commonly used industrial chemical that is known to be neurotoxic to mammals. However, its developmental toxicity is rarely assessed in mammalian models...
Acrylamide is a commonly used industrial chemical that is known to be neurotoxic to mammals. However, its developmental toxicity is rarely assessed in mammalian models because of the cost and complexity involved. We used zebrafish to assess the neurotoxicity, developmental and behavioral toxicity of acrylamide. At 6 h post fertilization, zebrafish embryos were exposed to four concentrations of acrylamide (10, 30, 100, or 300 mg/L) in a medium for 114 h. Acrylamide caused developmental toxicity characterized by yolk retention, scoliosis, swim bladder deficiency, and curvature of the body. Acrylamide also impaired locomotor activity, which was measured as swimming speed and distance traveled. In addition, treatment with 100 mg/L acrylamide shortened the width of the brain and spinal cord, indicating neuronal toxicity. In summary, acrylamide induces developmental toxicity and neurotoxicity in zebrafish. This can be used to study acrylamide neurotoxicity in a rapid and cost-efficient manner.
Topics: Acrylamide; Air Sacs; Animals; Animals, Genetically Modified; Disease Models, Animal; Embryo, Nonmammalian; Embryonic Development; Neurotoxicity Syndromes; Scoliosis; Swimming; Zebrafish
PubMed: 33805345
DOI: 10.3390/ijms22073518 -
Proceedings of the National Academy of... May 2023Western dietary patterns have been unfavorably linked with mental health. However, the long-term effects of habitual fried food consumption on anxiety and depression and...
Western dietary patterns have been unfavorably linked with mental health. However, the long-term effects of habitual fried food consumption on anxiety and depression and underlying mechanisms remain unclear. Our population-based study with 140,728 people revealed that frequent fried food consumption, especially fried potato consumption, is strongly associated with 12% and 7% higher risk of anxiety and depression, respectively. The associations were more pronounced among male and younger consumers. Consistently, long-term exposure to acrylamide, a representative food processing contaminant in fried products, exacerbates scototaxis and thigmotaxis, and further impairs exploration ability and sociality of adult zebrafish, showing anxiety- and depressive-like behaviors. Moreover, treatment with acrylamide significantly down-regulates the gene expression of related to the permeability of blood-brain barrier. Multiomics analysis showed that chronic exposure to acrylamide induces cerebral lipid metabolism disturbance and neuroinflammation. PPAR signaling pathway mediates acrylamide-induced lipid metabolism disorder in the brain of zebrafish. Especially, chronic exposure to acrylamide dysregulates sphingolipid and phospholipid metabolism, which plays important roles in the development of anxiety and depression symptoms. In addition, acrylamide promotes lipid peroxidation and oxidation stress, which participate in cerebral neuroinflammation. Acrylamide dramatically increases the markers of lipid peroxidation, including (±)5-HETE, 11(S)-HETE, 5-oxoETE, and up-regulates the expression of proinflammatory lipid mediators such as (±)12-HETE and 14(S)-HDHA, indicating elevated cerebral inflammatory status after chronic exposure to acrylamide. Together, these results both epidemiologically and mechanistically provide strong evidence to unravel the mechanism of acrylamide-triggered anxiety and depression, and highlight the significance of reducing fried food consumption for mental health.
Topics: Male; Animals; Zebrafish; Lipid Metabolism; Depression; Neuroinflammatory Diseases; Acrylamide; Anxiety; Food Contamination
PubMed: 37094155
DOI: 10.1073/pnas.2221097120 -
Targeted Oncology Mar 2021In the global FLAURA study, first-line osimertinib, a third-generation irreversible tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR),... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the global FLAURA study, first-line osimertinib, a third-generation irreversible tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), significantly improved progression-free survival (PFS) and overall survival (OS) versus comparator EGFR TKIs in patients with EGFR mutation-positive (EGFRm) advanced non-small-cell lung cancer (NSCLC).
OBJECTIVE
The FLAURA China study assessed first-line osimertinib in Chinese patients with EGFRm advanced NSCLC (NCT02296125).
METHODS
FLAURA China was a double-blind, randomized, phase III study. Adults from mainland China with previously untreated EGFRm (Exon 19 deletion or L858R) advanced NSCLC were enrolled in the global study or a China-only study under the same protocol; 136 patients were randomized to osimertinib (80 mg once daily [od]; n = 71) or comparator EGFR TKI (gefitinib or erlotinib; all sites selected gefitinib 250 mg od; n = 65). Patients were randomized and allocated to treatment groups by a central computer system. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed PFS; OS was a secondary endpoint.
RESULTS
All 136 randomized patients were analyzed. Osimertinib extended median PFS by 8.0 months versus comparator EGFR TKI (17.8 vs. 9.8 months; hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.37-0.85). Median OS was 33.1 months in the osimertinib group versus 25.7 months in the comparator group (HR 0.85; 95% CI 0.56-1.29). At 3 years, 20% of patients on osimertinib and 8% on the comparator remained on randomized treatment. Grade 3 or higher adverse events (AEs) were reported in 54 and 28% of patients in the osimertinib and comparator groups, respectively, driven by increased local reporting of laboratory- and disease-related AEs. No new safety signals were identified.
CONCLUSIONS
First-line osimertinib treatment resulted in a clinically meaningful PFS and OS benefit versus comparator EGFR TKI in Chinese patients with EGFRm advanced NSCLC. Safety data were consistent with the known safety profile of osimertinib.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov NCT02296125, registered 20 November 2014.
Topics: Acrylamides; Adult; Aged; Aged, 80 and over; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; China; Double-Blind Method; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors
PubMed: 33544337
DOI: 10.1007/s11523-021-00794-6 -
Science (New York, N.Y.) Jan 2015In optical microscopy, fine structural details are resolved by using refraction to magnify images of a specimen. We discovered that by synthesizing a swellable polymer...
In optical microscopy, fine structural details are resolved by using refraction to magnify images of a specimen. We discovered that by synthesizing a swellable polymer network within a specimen, it can be physically expanded, resulting in physical magnification. By covalently anchoring specific labels located within the specimen directly to the polymer network, labels spaced closer than the optical diffraction limit can be isotropically separated and optically resolved, a process we call expansion microscopy (ExM). Thus, this process can be used to perform scalable superresolution microscopy with diffraction-limited microscopes. We demonstrate ExM with apparent ~70-nanometer lateral resolution in both cultured cells and brain tissue, performing three-color superresolution imaging of ~10(7) cubic micrometers of the mouse hippocampus with a conventional confocal microscope.
Topics: Acrylamide; Acrylamides; Acrylates; Animals; Coated Pits, Cell-Membrane; Fluorescent Dyes; Gels; HEK293 Cells; Hippocampus; Humans; Mice, Inbred C57BL; Mice, Transgenic; Microscopy; Microscopy, Confocal; Microscopy, Fluorescence; Microtubules; Optical Imaging; Polymers; Tissue Fixation
PubMed: 25592419
DOI: 10.1126/science.1260088 -
Journal of Physiology and Pharmacology... Dec 2018Acrylamide (ACR) is a chemical compound, that forms in starchy food products during cooking at high-temperatures, including frying, baking, and roasting. ACR is a known... (Review)
Review
Acrylamide (ACR) is a chemical compound, that forms in starchy food products during cooking at high-temperatures, including frying, baking, and roasting. ACR is a known lethal neurotoxin. The presented review suggests that the mechanism of ACR's neurotoxicity may be related to an impaired cholinergic transmission in the central and peripheral nervous system and redox imbalance. These may not only affect ongoing brain functions but also participate in etiology of neurodegeneration.
Topics: Acrylamide; Animals; Cholinergic Agents; Humans; Nervous System; Neurotoxins
PubMed: 30898983
DOI: 10.26402/jpp.2018.6.03 -
JAMA Oncology Nov 2018Osimertinib mesylate is used globally to treat EGFR-mutant non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M...
IMPORTANCE
Osimertinib mesylate is used globally to treat EGFR-mutant non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M mutation. Acquired resistance to osimertinib is a growing clinical challenge that is poorly understood.
OBJECTIVE
To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior.
DESIGN, SETTING, AND PARTICIPANTS
Patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor were identified from a multi-institutional cohort (n = 143) and a confirmatory trial cohort (NCT01802632) (n = 110). Next-generation sequencing of tumor biopsies after osimertinib resistance was performed. Genotyping of plasma cell-free DNA was studied as an orthogonal approach, including serial plasma samples when available. The study and analysis were finalized on November 9, 2017.
MAIN OUTCOMES AND MEASURES
Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib.
RESULTS
Of the 143 patients evaluated, 41 (28 [68%] women) had tumor next-generation sequencing after acquired resistance to osimertinib. Among 13 patients (32%) with maintained T790M at the time of resistance, EGFR C797S was seen in 9 patients (22%). Among 28 individuals (68%) with loss of T790M, a range of competing resistance mechanisms was detected, including novel mechanisms such as acquired KRAS mutations and targetable gene fusions. Time to treatment discontinuation was shorter in patients with T790M loss (6.1 vs 15.2 months), suggesting emergence of pre-existing resistant clones; this finding was confirmed in a validation cohort of 110 patients with plasma cell-free DNA genotyping performed after osimertinib resistance. In studies of serial plasma levels of mutant EGFR, loss of T790M at resistance was associated with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease; P = .01).
CONCLUSIONS AND RELEVANCE
Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance.
Topics: Acrylamides; Aniline Compounds; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms
PubMed: 30073261
DOI: 10.1001/jamaoncol.2018.2969 -
Comprehensive Reviews in Food Science... Mar 2021Acrylamide is the product of the Maillard reaction, which occurs when starchy, asparagine-rich foods including potato or grain products and coffee are fried, baked,... (Review)
Review
Acrylamide is the product of the Maillard reaction, which occurs when starchy, asparagine-rich foods including potato or grain products and coffee are fried, baked, roasted, or heated. Studies in rodents provide evidence that acrylamide is carcinogenic and a male reproductive harmful agent when administered in exceedingly high levels. A 2002 study identified acrylamide in popular consumer food and beverage products, stimulating the European Union (EU) and California to legislate public notice of acrylamide presence in fried and baked foods, and coffee products. The regulatory legislation enacted in the EU and California has scientists working to develop foods and processes aimed at reducing acrylamide formation and advancing rapid and accurate analytical methods for the quantitative and qualitative determination of acrylamide in food and beverage products. The purpose of this review is to survey the studies performed on rodents and humans that identified the potential health impact of acrylamide in the human diet, and provide insight into established and emerging analytical methods used to detect acrylamide in blood, aqueous samples, and food.
Topics: Acrylamide; Coffee; Edible Grain; Food Contamination; Solanum tuberosum
PubMed: 33484492
DOI: 10.1111/1541-4337.12696 -
Food and Chemical Toxicology : An... Mar 2022Acrylamide forms in many commonly consumed foods. In animals, acrylamide causes tumors, neurotoxicity, developmental and reproductive effects. Acrylamide crosses the... (Review)
Review
Acrylamide forms in many commonly consumed foods. In animals, acrylamide causes tumors, neurotoxicity, developmental and reproductive effects. Acrylamide crosses the placenta and has been associated with restriction of intrauterine growth and certain cancers. The impact on human health is poorly understood and it is impossible to say what level of dietary exposure to acrylamide can be deemed safe as the assessment of exposure is uncertain. The determination of hemoglobin (Hb) adducts from acrylamide is increasingly being used to improve the exposure assessment of acrylamide. We aim to outline the literature on Hb adduct levels from acrylamide in humans and discuss methodological issues and research gaps. A total of 86 studies of 27,966 individuals from 19 countries were reviewed. Adduct levels were highest in occupationally exposed individuals and smokers. Levels ranged widely from 3 to 210 pmol/g Hb in non-smokers from the general population and this wide range suggests that dietary exposure to acrylamide varies largely. Non-smokers from the US and Canada had slightly higher levels as compared with non-smokers from elsewhere, but differences within studies were larger than between studies. Large studies with exposure assessment of acrylamide and related adduct forming compounds from diet during early-life are encouraged for the evaluation of health effects.
Topics: Acrylamide; Food Contamination; Hemoglobins; Humans; Risk Factors; Smoking
PubMed: 34995709
DOI: 10.1016/j.fct.2021.112799 -
Journal of Agricultural and Food... Apr 2022Widely consumed thermally processed corn-based foods can have a great contribution to acrylamide dietary intake, thus bearing a high public health risk and requiring... (Review)
Review
Widely consumed thermally processed corn-based foods can have a great contribution to acrylamide dietary intake, thus bearing a high public health risk and requiring attention and application of strategies for its reduction. This paper reviews the literature on the acrylamide content of corn-based food products present in the market around the world. The potential of corn for acrylamide formation due to its content of free asparagine and reducing sugars is described. Human exposure to acrylamide from corn-based foods is also discussed. The content of acrylamide in corn/tortilla chips, popcorn, and corn flakes, as widely consumed products all over the world, is reported in the literature to be between 5 and 6360 μg/kg, between
acrylamide sources in the common diet of all age populations, higher intake values occurred among younger generations. Topics: Acrylamide; Fast Foods; Food Contamination; Food Handling; Humans; Zea mays
PubMed: 35357820
DOI: 10.1021/acs.jafc.1c07249 -
Scientific Reports Jul 2022Acrylamide is a chemical used in various industries and a product following high-temperature cooking of vegetables containing asparagine. Environmental or dietary...
Acrylamide is a chemical used in various industries and a product following high-temperature cooking of vegetables containing asparagine. Environmental or dietary exposure to acrylamide could impair cognitive function because of its neurotoxicity. Using rat hippocampal slices, we tested whether acrylamide alters induction of long-term potentiation (LTP), a cellular model of learning and memory. We hypothesized that acrylamide impairs cognitive function via activation of pro-inflammatory cytokines because robust upregulation of NLRP3 inflammasome has been reported. Although acrylamide up to 3 mM did not alter basal synaptic transmission, incubation with 10 μM or acute administration of 100 μM acrylamide inhibited induction of LTP. Inhibitors of toll-like receptor 4 (TLR4), and minocycline, an inhibitor of microglial activation, overcame the effects of acrylamide on LTP induction. Furthermore, we observed that acrylamide failed to inhibit LTP after administration of MCC950, an inhibitor of NLRP3, or in the presence of Interleukin-1 receptor antagonist (IL-1Ra). We also found that in vivo acrylamide injection transiently impaired body weight gain and impaired one-trial inhibitory avoidance learning. This learning deficit was overcome by MCC950. These results indicate that cognitive impairment by acrylamide is mediated by mechanisms involving microglia and release of cytokines via NLRP3 activation.
Topics: Acrylamide; Animals; Cytokines; Hippocampus; Long-Term Potentiation; Microglia; NLR Family, Pyrin Domain-Containing 3 Protein; Rats
PubMed: 35858988
DOI: 10.1038/s41598-022-16762-7