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1.
Arch Toxicol ; 96(1): 335-365, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34687351

RESUMO

Polybrominated diphenyl ethers (PBDEs) are ubiquitous persistent organic pollutants (POPs) that are known neuroendocrine disrupting chemicals with adverse neurodevelopmental effects. PBDEs may act as risk factors for autism spectrum disorders (ASD), characterized by abnormal psychosocial functioning, although direct evidence is currently lacking. Using a translational exposure model, we tested the hypothesis that maternal transfer of a commercial mixture of PBDEs, DE-71, produces ASD-relevant behavioral and neurochemical deficits in female offspring. C57Bl6/N mouse dams (F0) were exposed to DE-71 via oral administration of 0 (VEH/CON), 0.1 (L-DE-71) or 0.4 (H-DE-71) mg/kg bw/d from 3 wk prior to gestation through end of lactation. Mass spectrometry analysis indicated in utero and lactational transfer of PBDEs (in ppb) to F1 female offspring brain tissue at postnatal day (PND) 15 which was reduced by PND 110. Neurobehavioral testing of social novelty preference (SNP) and social recognition memory (SRM) revealed that adult L-DE-71 F1 offspring display deficient short- and long-term SRM, in the absence of reduced sociability, and increased repetitive behavior. These effects were concomitant with reduced olfactory discrimination of social odors. Additionally, L-DE-71 exposure also altered short-term novel object recognition memory but not anxiety or depressive-like behavior. Moreover, F1 L-DE-71 displayed downregulated mRNA transcripts for oxytocin (Oxt) in the bed nucleus of the stria terminalis (BNST) and supraoptic nucleus, and vasopressin (Avp) in the BNST and upregulated Avp1ar in BNST, and Oxtr in the paraventricular nucleus. Our work demonstrates that developmental PBDE exposure produces ASD-relevant neurochemical, olfactory processing and behavioral phenotypes that may result from early neurodevelopmental reprogramming within central social and memory networks.


Assuntos
Transtorno Autístico , Retardadores de Chama , Neuropeptídeos , Animais , Feminino , Éteres Difenil Halogenados/toxicidade , Humanos , Exposição Materna/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo
2.
Life Sci ; 289: 120094, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34710444

RESUMO

AIMS: To characterize exercise fatigue, metabolic phenotype and cognitive and mood deficits correlated with brain neuroinflammatory and gut microbiome changes in a chronic Gulf War Illness (GWI) mouse model. The latter have been described in an accompanying paper [1]. MAIN METHODS: Adult male C57Bl/6N mice were exposed for 28 days (5 days/week) to pyridostigmine bromide: 6.5 mg/kg, b.i.d., P.O. (GW1) or 8.7 mg/kg, q.d., P.O. (GW2); topical permethrin (1.3 mg/kg in 100% DMSO) and N,N-diethyl-meta-toluamide (DEET 33% in 70% EtOH) and restraint stress (5 min). Exercise, metabolic and behavioral endpoints were compared to sham stress control (CON/S). KEY FINDINGS: Relative to CON/S, GW2 presented persistent exercise intolerance (through post-treatment (PT) day 161), deficient associative learning/memory, and transient insulin insensitivity. In contrast to GW2, GW1 showed deficient long-term object recognition memory, milder associative learning/memory deficit, and behavioral despair. SIGNIFICANCE: Our findings demonstrate that GW chemicals dose-dependently determine the presentation of exercise fatigue and severity/type of cognitive/mood-deficient phenotypes that show persistence. Our comprehensive mouse model of GWI recapitulates the major multiple symptom domains characterizing GWI, including fatigue and cognitive impairment that can be used to more efficiently develop diagnostic tests and curative treatments for ill Gulf War veterans.


Assuntos
Fadiga , Glucose/metabolismo , Deficiências da Aprendizagem , Síndrome do Golfo Pérsico , Brometo de Piridostigmina/efeitos adversos , Animais , Modelos Animais de Doenças , Fadiga/induzido quimicamente , Fadiga/metabolismo , Fadiga/patologia , Humanos , Deficiências da Aprendizagem/induzido quimicamente , Deficiências da Aprendizagem/metabolismo , Deficiências da Aprendizagem/patologia , Masculino , Camundongos , Síndrome do Golfo Pérsico/induzido quimicamente , Síndrome do Golfo Pérsico/metabolismo , Síndrome do Golfo Pérsico/patologia , Brometo de Piridostigmina/farmacologia
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