Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON, Canada.
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON, Canada.
Alcohol Clin Exp Res. 2021 Jul;45(7):1383-1397. doi: 10.1111/acer.14631. Epub 2021 Jun 4.
Prenatal alcohol exposure (PAE) can result in developmental defects that include growth restriction, craniofacial anomalies, and cognitive behavioral deficits, though the presence and severity of these adverse outcomes can vary dramatically among exposed individuals. Preclinical animal models have demonstrated that the dose and timing of PAE account for much, but not all, of this phenotypic variation, suggesting that additional factors mitigate the effects of PAE. Here, we used a mouse model to investigate whether maternal age modulates the effects of PAE on the severity and variation in offspring growth and craniofacial outcomes.
Nulliparous C57BL/6N dams received either an intraperitoneal injection of ethanol (EtOH) or vehicle solution on gestational day 7.5. Dams were divided into four groups: (1) EtOH-treated young dams (6 to 10 weeks); (2) control young dams; (3) EtOH-treated old dams (6 to 7 months); and (4) old control dams. Neonate offspring growth restriction was measured through body mass and organ-to-body mass ratios, while skeletal craniofacial features were imaged using micro-CT and analyzed for size, shape, and variation.
PAE and advanced maternal age each increased the risk of low birthweight and growth restriction in offspring, but these factors in combination changed the nature of the growth restriction. Similarly, both PAE and advanced maternal age individually caused changes to craniofacial morphology such as smaller skull size, dysmorphic skull shape, and greater skull shape variation and asymmetry. Interestingly, while the combination of PAE and advanced maternal age did not affect mean skull shape or size, it significantly increased the variation and asymmetry of those measures.
Our results indicate that maternal age modulates the effects of PAE, but that the effects of this combination on offspring outcomes are more complex than simply scaling the effects of either factor.
产前酒精暴露 (PAE) 可导致发育缺陷，包括生长受限、颅面异常和认知行为缺陷，尽管暴露个体中这些不良后果的存在和严重程度可能有很大差异。临床前动物模型表明，PAE 的剂量和时间对这种表型变异有很大影响，但并非全部，这表明其他因素减轻了 PAE 的影响。在这里，我们使用小鼠模型来研究母体年龄是否调节 PAE 对后代生长和颅面结局严重程度和变异性的影响。
初产 C57BL/6N 母鼠在妊娠第 7.5 天接受腹腔内注射乙醇 (EtOH) 或载体溶液。将母鼠分为四组：（1）EtOH 处理的年轻母鼠（6-10 周）；（2）对照年轻母鼠；（3）EtOH 处理的老年母鼠（6-7 个月）；和（4）老年对照母鼠。通过体重和器官与体重比来测量新生仔鼠生长受限，而骨骼颅面特征则使用 micro-CT 成像，并分析大小、形状和变异性。
PAE 和母鼠高龄都增加了后代低出生体重和生长受限的风险，但这些因素的组合改变了生长受限的性质。同样，PAE 和母鼠高龄单独都会导致颅面形态发生变化，例如颅骨尺寸减小、颅骨形状畸形以及颅骨形状变化和不对称性增加。有趣的是，虽然 PAE 和母鼠高龄的组合对平均颅骨形状或大小没有影响，但它显著增加了这些指标的变异性和不对称性。
我们的结果表明，母体年龄调节 PAE 的影响，但这种组合对后代结局的影响比简单地放大任何因素的影响更为复杂。
