Autism, a childhood behavioral disorder, belongs to a large suite of diseases, collectively referred to as autism spectrum disorders (ASD). Though multifactorial in etiology, approximately 10% of ASD are associated with atopic dermatitis (AD). Moreover, ASD prevalence increases further as AD severity worsens, though these disorders share no common causative mutations. We assessed here the link between these two disorders in the standard, valproic acid mouse model of ASD. In prior studies, there was no evidence of skin involvement, but we hypothesized that cutaneous involvement could be detected in experiments conducted in BALB/c mice. BALB/c is an albino, laboratory-bred strain of the house mouse and is among the most widely used inbred strains used in animal experimentation. We performed our studies in valproic acid (VPA)-treated BALB/c hairless mice, a standard mouse model of ASD. Mid-trimester pregnant mice received a single intraperitoneal injection of either valproic acid sodium salt dissolved in saline or saline alone on embryonic day 12.5 and were housed individually until postnatal day 21. Only the brain and epidermis appeared to be affected, while other tissues remain unchanged. At various postnatal time points, brain, skin and blood samples were obtained for histology and for quantitation of tissue sphingolipid content and cytokine levels. AD-like changes in ceramide content occurred by day one postpartum in both VPA-treated mouse skin and brain. The temporal co-emergence of AD and ASD, and the AD phenotype-dependent increase in ASD prevalence correlated with early appearance of cytokine markers (i.e., interleukin [IL]-4, 5, and 13), as well as mast cells in skin and brain. The high levels of interferon (IFN)γ not only in skin, but also in brain likely account for a significant decline in esterified very-long-chain N-acyl fatty acids in brain ceramides, again mimicking known IFNγ-induced changes in AD. Baseline involvement of both AD and ASD could reflect concurrent neuro- and epidermal toxicity, possibly because both epidermis and neural tissues originate from the embryonic neuroectoderm. These studies illuminate the shared susceptibility of the brain and epidermis to a known neurotoxin, suggesting that the atopic diathesis could be extended to include ASD.

中文翻译：

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特应性皮炎和自闭症之间的表型重叠


自闭症是一种儿童行为障碍，属于一大类疾病，统称为自闭症谱系障碍 (ASD)。尽管 ASD 的病因是多因素的，但大约 10% 的 ASD 与特应性皮炎 (AD) 相关。此外，随着 AD 严重程度的恶化，自闭症谱系障碍（ASD）患病率进一步增加，尽管这些疾病没有共同的致病突变。我们在此评估了标准丙戊酸 ASD 小鼠模型中这两种疾病之间的联系。在之前的研究中，没有皮肤受累的证据，但我们假设在 BALB/c 小鼠中进行的实验中可以检测到皮肤受累。 BALB/c 是一种实验室饲养的白化家鼠品系，是动物实验中使用最广泛的近交品系之一。我们在丙戊酸 (VPA) 治疗的 BALB/c 无毛小鼠（自闭症谱系障碍的标准小鼠模型）中进行了研究。妊娠中期小鼠在胚胎第 12.5 天接受单次腹腔注射溶解在盐水中的丙戊酸钠盐或单独的盐水，并单独饲养直至出生后第 21 天。只有大脑和表皮似乎受到影响，而其他组织保持不变。在出生后的不同时间点，获取脑、皮肤和血液样本用于组织学分析以及组织鞘脂含量和细胞因子水平的定量。产后第一天，经 VPA 处理的小鼠皮肤和大脑中的神经酰胺含量发生了类似 AD 的变化。 AD 和 ASD 在时间上同时出现，以及 AD 表型依赖性 ASD 患病率增加与细胞因子标记物（即白细胞介素 [IL]-4、5 和 13）以及皮肤中肥大细胞的早期出现相关和大脑。 不仅皮肤中存在高水平的干扰素 (IFN)γ，大脑中的干扰素 (IFN)γ 水平也可能导致脑神经酰胺中酯化的极长链 N-酰基脂肪酸显着下降，这再次模仿了已知的 IFNγ 诱导的 AD 变化。 AD 和 ASD 的基线受累可以反映同时发生的神经和表皮毒性，可能是因为表皮和神经组织都起源于胚胎神经外胚层。这些研究阐明了大脑和表皮对已知神经毒素的共同敏感性，表明特应性素质可以扩展到包括 ASD。