Schambra Uta B, Nunley Kevin, Harrison Theresa A, Lewis C Nicole
Department Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
Department Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
Neurotoxicol Teratol. 2016 Sep-Oct;57:39-53. doi: 10.1016/j.ntt.2016.06.003. Epub 2016 Jun 11.
In a previous study we used a mouse model for ethanol exposure during gastrulation or neurulation to investigate the effects of modest and occasional human drinking during the 3rd or 4th week of pregnancy (Schambra et al., 2015). Pregnant C57Bl/6J mice were treated by gavage during gastrulation on gestational day (GD) 7 or neurulation on GD8 with 2 doses 4h apart of either 2.4 or 2.9g ethanol/kg body weight, resulting in peak blood ethanol concentrations (BECs) of 104 and 177mg/dl, respectively. We found that mice exposed to the low dose on either day were significantly delayed in their neonatal sensorimotor development. In the present study, we tested the same cohort of mice in an open field as juveniles on postnatal day (PD) 23-25 and as young adults on PD65-67 for prenatal ethanol effects on exploration and emotionality with measures of activity, rearing, grooming and defecation. We evaluated the effects of dose, sex, day of treatment and day of birth by multiple regression analyses. We found that, compared to the respective gavage controls, juvenile mice that had been prenatally exposed to the low BEC on either GD7 or GD8 were significantly hypoactive on the first 2 test days, reared significantly more on the last 2 test days, and groomed and defecated significantly more on all 3 test days. Only mice that had been treated on GD7 remained hypoactive as adults. Juvenile mice prenatally exposed to the moderate BEC on GD7 groomed significantly more, while those exposed on GD8 reared and defecated significantly more. Sex differences were highly significant in adult control mice, with control males less active and more emotional than females. Similar, but smaller, sex differences were also evident in adults exposed to ethanol prenatally. Persistence into later life of a deleterious effect of premature birth (i.e., birth on GD19 rather than GD20) on weight and behavior was not consistently supported by these data. Importantly, mice shown previously to be delayed in sensorimotor development as neonates, in the present study demonstrated hypoactivity and increased emotionality in open field behaviors as juveniles, and those mice exposed during gastrulation remained hypoactive as adults. Thus, we propose that the delayed motor development, hypoactivity and emotionality we observed in mice exposed to a low BEC during gastrulation or neurulation may relate to an attention deficit-activity disorder in humans, possibly the inattentive subtype, or Sluggish Cognitive Tempo (SCT). We further discuss concerns about occasional light or moderate alcohol consumption during the 3rd or 4th week of human pregnancy.
在之前的一项研究中，我们使用了一个小鼠模型，该模型在原肠胚形成期或神经胚形成期接触乙醇，以研究在妊娠第3或第4周偶尔适度饮酒对人类的影响（Schambra等人，2015年）。妊娠的C57Bl/6J小鼠在妊娠第7天原肠胚形成期或第8天神经胚形成期通过灌胃处理，相隔4小时给予2.4或2.9克乙醇/千克体重的两个剂量，导致血液乙醇浓度峰值（BECs）分别为104和177毫克/分升。我们发现，在这两天中任何一天接触低剂量乙醇的小鼠，其新生儿感觉运动发育都显著延迟。在本研究中，我们在出生后第23 - 25天作为幼鼠以及在出生后第65 - 67天作为年轻成年鼠，在旷场实验中测试了同一组小鼠，以研究产前乙醇暴露对探索和情绪方面的影响，测量指标包括活动、竖毛、理毛和排便。我们通过多元回归分析评估了剂量、性别、处理日和出生日的影响。我们发现，与各自的灌胃对照组相比，在妊娠第7天或第8天产前暴露于低BEC的幼鼠在最初2个测试日显著活动减少，在最后2个测试日竖毛显著增多，并且在所有3个测试日理毛和排便显著增多。只有在妊娠第7天接受处理的小鼠成年后仍活动减少。在妊娠第7天产前暴露于中度BEC的幼鼠理毛显著增多，而在第8天暴露的幼鼠竖毛和排便显著增多。成年对照小鼠中性别差异非常显著，对照雄性比雌性活动更少且更情绪化。在产前暴露于乙醇的成年小鼠中也存在类似但较小的性别差异。早产（即妊娠第19天而非第20天出生）对体重和行为的有害影响持续到成年期，这些数据并未一致支持这一点。重要的是，之前显示为新生儿时感觉运动发育延迟的小鼠，在本研究中表现为幼鼠在旷场行为中活动减少且情绪性增加，并且在原肠胚形成期接触乙醇的那些小鼠成年后仍活动减少。因此，我们提出，在原肠胚形成期或神经胚形成期接触低BEC的小鼠中观察到的运动发育延迟、活动减少和情绪性增加，可能与人类的注意力缺陷 - 活动障碍有关，可能是注意力不集中亚型，或缓慢认知节奏（SCT）。我们进一步讨论了关于人类妊娠第3或第4周偶尔轻度或中度饮酒的问题。
