Uban K A, Herting M M, Wozniak J R, Sowell E R
Department of Pediatrics, Children's Hospital Los Angeles/University of Southern California, Los Angeles, CA, USA.
Department of Pediatrics, Children's Hospital Los Angeles/University of Southern California, Los Angeles, CA, USA; Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Psychoneuroendocrinology. 2017 Sep;83:111-121. doi: 10.1016/j.psyneuen.2017.05.019. Epub 2017 May 26.
Despite accumulating evidence from animal models demonstrating that prenatal alcohol exposure (PAE) results in life-long neuroendocrine dysregulation, very little is known on this topic among humans with fetal alcohol spectrum disorders (FASD). We expected that alterations in gonadal hormones might interfere with the typical development of white matter (WM) myelination, and in a sex-dependent manner, in human adolescents with FASD. In order to investigate this hypothesis, we used diffusion tensor imaging (DTI) to assess: 1) whether or not sex moderates the impact of PAE on WM microstructure; and 2) how gonadal hormones relate to alterations in WM microstructure in children and adolescents affected by PAE.
61 youth (9 to 16 yrs.; 49% girls; 50% PAE) participated as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD). DTI scans and passive drool samples were obtained to examine neurodevelopmental associations with testosterone (T) and dehydroepiandrosterone (DHEA) levels in boys and girls, and estradiol (E2) and progesterone (P) levels in girls. Tract-based spatial statistics were utilized to generate fractional anisotropy (FA) and mean diffusivity (MD) for 9 a priori WM regions of interest (ROIs).
As predicted, alterations in FA were observed in adolescents with PAE relative to controls, and these differences varied by sex. Girls with PAE exhibited lower FA (Inferior fronto-occipital and Uncinate fasciculi) while boys with PAE exhibited higher FA (Callosal body, Cingulum, Corticospinal tract, Optic radiation, Superior longitudinal fasciculus) relative to age-matched controls. When gonadal hormone levels were examined in relation to DTI measures, additional group differences in FA were revealed, demonstrating that neuroendocrine factors are associated with PAE-related brain alterations.
These findings provide human evidence that PAE relates to sex-specific differences in WM microstructure, and underlying alterations in gonadal hormone function may, in part, contribute to these effects. Determining PAE-effects on neuroendocrine function among humans is an essential first step towards developing novel clinical (e.g., assessment or intervention) tools that target hormone systems to improve on-going brain development among children and adolescents with FASD.
尽管动物模型积累的证据表明产前酒精暴露（PAE）会导致终身神经内分泌失调，但在患有胎儿酒精谱系障碍（FASD）的人类中，关于这一主题的了解却非常少。我们预期性腺激素的改变可能会干扰FASD青少年白质（WM）髓鞘形成的典型发育，且存在性别差异。为了验证这一假设，我们使用扩散张量成像（DTI）来评估：1）性别是否会调节PAE对WM微观结构的影响；2）性腺激素与受PAE影响的儿童和青少年WM微观结构改变之间的关系。
61名青少年（9至16岁；49%为女孩；50%有PAE）作为胎儿酒精谱系障碍合作倡议（CIFASD）的一部分参与研究。获取DTI扫描和被动流涎样本，以检查男孩和女孩的睾酮（T）和脱氢表雄酮（DHEA）水平以及女孩的雌二醇（E2）和孕酮（P）水平与神经发育的关联。基于体素的空间统计学方法用于生成9个先验WM感兴趣区域（ROI）的分数各向异性（FA）和平均扩散率（MD）。
正如预期，与对照组相比，PAE青少年的FA出现改变，且这些差异因性别而异。与年龄匹配的对照组相比，有PAE的女孩FA较低（额枕下束和钩束），而有PAE的男孩FA较高（胼胝体、扣带束、皮质脊髓束、视辐射、上纵束）。当检查性腺激素水平与DTI测量值的关系时，发现FA存在更多组间差异，表明神经内分泌因素与PAE相关的脑改变有关。
这些发现为PAE与WM微观结构的性别特异性差异有关提供了人体证据，性腺激素功能的潜在改变可能部分导致了这些影响。确定PAE对人类神经内分泌功能的影响是开发针对激素系统的新型临床（如评估或干预）工具的重要第一步，以改善FASD儿童和青少年正在进行的脑发育。
