Mechanisms underlying neuro-inflammation and neurodevelopmental toxicity in the mouse neocortex following prenatal exposure to ethanol

Abstract

Fetal alcohol spectrum disorders (FASD) constitute a wide range of disorders that arise from prenatal exposure to ethanol (EtOH). However, detailed reports regarding the adverse effects of prenatal EtOH exposure on neocortical morphology and its underlying pathogenic mechanisms are limited. In the present study, we aimed to characterize the anatomical abnormalities of neocortical development and their correlation with microglial properties and neuro-inflammation in a mouse model of FASD. We evaluated the development and maturation of the neocortex in ICR mice prenatally exposed to 25% (w/v) EtOH using histological and molecular analyses. Reduced proliferation and excessive cell death were observed in the dorsal telencephalon. Abnormal neuronal distribution, layer formation, and dopaminergic neuronal projections were observed in the neocortex. Disruption of microglial differentiation (M1/M2 microglial ratio) and abnormal expression of pro-inflammatory and neurotrophic factors were induced, and these abnormalities were ameliorated by co-treatment with an anti-inflammatory drug (pioglitazone). FASD model mice displayed histological abnormalities, microglial abnormalities, and neuro-inflammation in both the embryonic and newborn stages. Thus, anti-inflammatory therapeutics may provide a novel preventive approach for the treatment of FASD.

The neonicotinoids acetamiprid and imidacloprid impair neurogenesis and alter the microglial profile in the hippocampal dentate gyrus of mouse neonates

“…In our previous studies, mouse fetuses or newborns treated prenatally with bisphenol A, ethanol or valproic acid showed abnormal neurogenesis, neuronal distribution and layer formation, as well as increased microglial activation in the developing neocortex. These neuronal abnormalities were ameliorated by co‐treatment with an anti‐inflammatory drug, pioglitazone (Komada et al, ; Nagao, unpublished data). Furthermore, microglia promote neurogenesis (Ueno et al, ).…”

“…Next, the total number of DAPI‐stained cells and antibody‐positive cells were counted within the whole hippocampal DGs of two anatomically matched sections from each neonate using Adobe Photoshop CS4 software (Adobe Systems, San Jose, CA, USA). The counting and quantification were performed in accordance with previously reported methods (Komada et al, ; Komada et al, ). The immunolocalized cells were analyzed in a double‐blind manner.…”

Neurodevelopmental toxicity in the mouse neocortex following prenatal exposure to acetamiprid

“…In previous studies, mouse fetuses or newborns treated prenatally with bisphenol A or ethanol showed abnormal neurogenesis, neuronal distribution and layer formation, as well as increased microglial activation in the developing neocortex. These neuronal abnormalities were ameliorated by co‐treatment with an anti‐inflammatory drug (pioglitazone) (Komada et al, , Komada et al, ; Takahashi, Komada, Miyazawa, Goto, & Ikeda, ). During neocortical maturation, microglia play an important role in neuronal migration (Bilimoria & Stevens, ).…”

“…Numbers and distributions of young neurons in the neocortex were analyzed in anatomically matched sections from each newborn in accordance with previously described methods (Komada et al, 2012;Komada et al, 2014;Komada et al, 2017;Molyneauz, Arlotta, Hirata, Hibi, & Macklis, 2005). The entire cortical thickness on parasagittal sections was subdivided into ten 100 μm fractions (bins 1-10).…”

CCL2/CCR2 system in neuroepithelial radial glia progenitor cells: Involvement in stimulatory, sexually dimorphic effects of maternal ethanol on embryonic development of hypothalamic peptide neurons

“…There is strong clinical and preclinical evidence showing that maternal consumption or administration of ethanol during pregnancy has marked effects on brain development and behavioral function in offspring, contributing to an increased risk for alcohol use disorder [1][2][3][4][5]. While chronic ethanol at higher doses causes morphological and functional defects in neural development throughout the brain [6,7], lower doses actually stimulate neurogenesis while having little impact on apoptosis and gliogenesis [8][9][10]. Maternal intraoral administration of ethanol in rat, at low-to-moderate doses from embryonic day 10 (E10) to E15 during peak hypothalamic neurogenesis, increases in the offspring the density of neurons in the lateral hypothalamus (LH) that express the orexigenic neuropeptide, melanin-concentrating hormone (MCH), which is known to have a role in reward and motivated behavior [11,12].…”