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1.
Toxicology ; 428: 152299, 2019 12 01.
Article in English | MEDLINE | ID: mdl-31574244

ABSTRACT

Bisphenol A (BPA) is a ubiquitously distributed endocrine disrupting chemical (EDC). BPA exposure in humans has been a matter of concern due to its increased application in the products of day to day use. BPA has been reported to cause toxicity in almost all the vital organ systems even at a very low dose levels. It crosses the blood brain barrier and causes neurotoxicity. We studied the effect of BPA on the cerebral cortex of C57BL/6J mice and examined whether BPA exposure alters the expression of axonal and myelin structural proteins. Male mice were dosed orally to 40 µg and 400 µg BPA/kg body weight for 60 days. BPA exposure resulted in memory loss, muscle coordination deficits and allodynia. BPA exposure also caused degeneration of immature and mature oligodendrocytes as evaluated by decreased mRNA levels of 2',3'-cyclic nucleotide 3' phosphodiesterase (CNPase), nestin, myelin basic protein (MBP) and myelin-associated glycoprotein-1 (MAG-1) genes revealing myelin related pathology. It was observed that subchronic BPA exposure caused neuroinflammation through deregulation of inflammatory cytokines mRNA and protein expression which further resulted into neurotoxicity through axonal as well as myelin degeneration in the brain. BPA also caused increased oxidative stress in the brain. Our study indicates long-term subchronic low dose exposure to BPA has the potential to cause axonal degeneration and demyelination in the oligodendrocytes and neurons which may have implications in neurological and neuropsychological disorders including multiple sclerosis (MS), neuromyelitis optica and others.


Subject(s)
Benzhydryl Compounds/toxicity , Endocrine Disruptors/toxicity , Neurotoxicity Syndromes , Phenols/toxicity , 2',3'-Cyclic-Nucleotide Phosphodiesterases/genetics , Animals , Ataxia/chemically induced , Ataxia/genetics , Ataxia/metabolism , Axons/drug effects , Behavior, Animal/drug effects , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cytokines/genetics , Cytokines/metabolism , Hyperalgesia/chemically induced , Hyperalgesia/genetics , Hyperalgesia/metabolism , Male , Memory/drug effects , Mice, Inbred C57BL , Myelin Basic Protein/genetics , Myelin Sheath/drug effects , Myelin-Associated Glycoprotein/genetics , Neurotoxicity Syndromes/genetics , Neurotoxicity Syndromes/metabolism , Touch
2.
Neurochem Int ; 118: 166-175, 2018 09.
Article in English | MEDLINE | ID: mdl-29908256

ABSTRACT

Bisphenol A (BPA), a well-known xenoestrogen, is ubiquitously utilized in manufacturing of polycarbonated plastics. Convincing evidence suggests that BPA induces neurotoxicity and certain behavioral deficits. α-Lipoic acid (ALA) supplementation has shown protective effect against heart and liver diseases, diabetes, and neurological debility associated with aging. We studied the neuromodulatory effect of ALA against neurotoxicity of BPA in vitro in C8-D1A mouse astrocyte cell line and in vivo in C57BL/6J male mice. In vitro ALA (100 µM) protected cells from BPA (30 µM)-induced reactive oxygen species generation and increased activity of glial fibrillary acidic protein. ALA showed reduction in cell death in astrocytes treated with BPA. In vivo ALA (50 mg/kg) increased the neurospecific acetylcholinesterase activity and decreased the monoamine oxidase activity altered by BPA exposure (10 mg/kg, per os x 30 days). In addition to neuroprotective effects, ALA also showed protective effects against BPA-induced oxidative stress. We observed that ALA significantly replenished the declined neurobehavioral and cognitive performances, decreased muscle coordination and alerted short-term recognition memory in mice exposed to BPA. Our results suggest that ALA has a promising role in modulating BPA-induced neurotoxicity in C8-D1A mouse astrocyte cells as well as neurochemical and neurobehavioral deficits in C57BL/6J male mice and its antioxidant and free radical scavenging activities may in part be responsible for such an effect.


Subject(s)
Antioxidants/pharmacology , Benzhydryl Compounds/toxicity , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , Phenols/toxicity , Recognition, Psychology/drug effects , Thioctic Acid/pharmacology , Animals , Cells, Cultured , Male , Mice , Mice, Inbred C57BL , Oxidative Stress/physiology , Recognition, Psychology/physiology
3.
J Biol Chem ; 290(4): 1979-93, 2015 Jan 23.
Article in English | MEDLINE | ID: mdl-25451928

ABSTRACT

Heme proteins, which reversibly bind oxygen and display a particular fold originally identified in myoglobin (Mb), characterize the "hemoglobin (Hb) superfamily." The long known and widely investigated Hb superfamily, however, has been enriched by the discovery and investigation of new classes and members. Truncated Hbs typify such novel classes and exhibit a distinct two-on-two α-helical fold. The truncated Hb from the freshwater cyanobacterium Synechocystis exhibits hexacoordinate heme chemistry and bears an unusual covalent bond between the nonaxial His(117) and a heme porphyrin 2-vinyl atom, which remains tightly associated with the globin unlike any other. It seems to be the most stable Hb known to date, and His(117) is the dominant force holding the heme. Mutations of amino acid residues in the vicinity did not influence this covalent linkage. Introduction of a nonaxial His into sperm whale Mb at the topologically equivalent position and in close proximity to vinyl group significantly increased the heme stability of this prototype globin. Reversed phase chromatography, electrospray ionization-MS, and MALDI-TOF analyses confirmed the presence of covalent linkage in Mb I107H. The Mb mutant with the engineered covalent linkage was stable to denaturants and exhibited ligand binding and auto-oxidation rates similar to the wild type protein. This indeed is a novel finding and provides a new perspective to the evolution of Hbs. The successful attempt at engineering heme stability holds promise for the production of stable Hb-based blood substitute.


Subject(s)
Histidine/chemistry , Myoglobin/chemistry , Protein Engineering/methods , Synechocystis/chemistry , Amino Acid Sequence , Calorimetry, Differential Scanning , Circular Dichroism , Electron Spin Resonance Spectroscopy , Escherichia coli/metabolism , Heme/chemistry , Hemoglobins/chemistry , Hydrogen-Ion Concentration , Molecular Sequence Data , Mutagenesis, Site-Directed , Mutation , Recombinant Proteins/chemistry , Sequence Homology, Amino Acid , Spectrometry, Mass, Electrospray Ionization , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Truncated Hemoglobins/chemistry
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