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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.

INTRODUCTIONStudies with rodents show that prenatal exposure to some neurotoxicants adversely affects neonatal orientation, attention and motor maturity, as well as activity level, executive function, response inhibition and sensory processing later in life (Schneider et al., 2011). Although there have been a vast number of animal toxicological studies carried out on pregnant animals including embryos/fetuses and mature animals, there is a paucity of reports on animal toxicology studies utilizing newborn animals a few days after birth. To evaluate the neurotoxic effects of chemicals on newborns in rodents, we very recently developed a mouse newborn neurobehavioral testing method; it involves quantitative determination of a newborn animal's activity automatically using the tare function of an analytical balance. We have demonstrated that developmentally 10 mg/kg methylnitrosourea-treated ICR mice showed increases in motor behavior including crawling, pivoting, righting or tremors when estimating this activity by this testing method on postnatal day 1 (Nagao et al., 2013).Bisphenol A (BPA) is one of the environmental endocrine disruptors released by plastics and resin known to interfere with hormonal responses. During fetal life, the intrauterine environment is critical for normal development, and even small changes in the levels of hormones may lead to changes in brain histology and function, and consequently in behavior. Nuclear estrogen receptor binding assays indicate that BPA has at least a 10,000-fold lower affinity for the two estrogen nuclear receptors than 17β-estradiol. In isolation, these results would suggest that BPA at environmentally relevant levels of exposure would not pose a public health problem (Zoeller et al., 2012). However, low doses of BPA administered perinatally can modify explorative behavior and anxiety in rat (Fujimoto et al., 2013). It has been shown that perinatal BPA exposure disrupted sexually dimorphic behavior in the postnatal developmental period and in adult mice, when evaluated by the elevated plus maze test and the open field test (Gioiosa et al., 2013;Nakamura et al., 2012). In addition, mice treated with BPA prenatally were hyperactive, like attention-deficit hyperactivity disorder (ADHD), in these behavioral tests. The mode of action underlying these effects is unclear. Recently, we demonstrated that histological changes of the cortical plate were found in mouse fetuses exposed to a low dose of BPA (Komada et al., 2012), and that prenatally BPA-treated mice showed hyperplasia of layer 6b and abnormal neuronal distribution in the neocortex of newborn (our unpubNeurobehavioral evaluation of mouse newborns exposed prenatally to low-dose bisphenol A Kusumoto-cho, Chikusa-ku, Nagoya, Aichi 464-8650, Japan (Received December 18, 2013; Accepted January 16, 2014) ABSTRACT -There have been few neurobehavioral toxicology studies on newborn animals. Thus, we developed a mouse newborn behavioral testing method for evaluating the risk of neurotoxicity of environmental toxicants, ...

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