Prenatal exposure to the organophosphate insecticide chlorpyrifos enhances brain oxidative stress and prostaglandin E2 synthesis in a mouse model of idiopathic autism.
Prenatal exposure to the organophosphate insecticide chlorpyrifos enhances brain oxidative stress and prostaglandin E2 synthesis in a mouse model of idiopathic autism.
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DOI：
10.1186/s12974-016-0617-4
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发表时间：
2016-06-14
影响因子：
9.3
通讯作者：
Minghetti L
中科院分区：
文献类型：
--
作者：
De Felice A;Greco A;Calamandrei G;Minghetti L
自闭症谱系障碍 (ASD) 是一种多基因和多因素疾病，其中缺陷基因之间的复杂相互作用和早期暴露于环境压力源会影响正确的神经发育和大脑过程。有机磷杀虫剂，其中毒死蜱 (CPF) 是广泛传播的环境毒物，与神经行为缺陷和儿童自闭症谱系障碍发生风险增加相关。氧化应激和失调的免疫反应与有机磷神经发育效应和 ASD 发病机制有关。 BTBR T+tf/J 小鼠是一种经过充分研究的特发性自闭症模型，在 ASD 儿童中发现了一些行为和免疫学改变，我们最近表明 CPF 妊娠暴露强化了其中一些类似自闭症的特征。在本研究中，我们旨在调查妊娠期 CPF 给药的行为影响是否与大脑氧化应激增加和脂质介质谱改变有关。通过对 BTBR T+tf/J 和 C57Bl6/J 小鼠脑匀浆中的特定酶免疫测定法评估 F2-异前列腺素 (15-F2t-IsoP) 的脑水平，作为体内氧化应激的指标，以及前列腺素 E2 (PGE2) 的脑水平，前列腺素 E2 是免疫细胞和主要位于皮层和海马的特定谷氨酸能神经元群释放的主要花生四烯酸代谢物。妊娠期间暴露于媒介物或 CPF。在出生后不同阶段（PND 1、21 和 70）的雌雄小鼠中进行了测量。与 C57Bl6/J 小鼠相比，BTBR T+tf/J 小鼠出生时表现出更高的基线 15-F2t-IsoP 水平，表明氧化应激过程更大。使用 CPF 增强妊娠治疗，以品系和年龄依赖性方式增强 15-F2t-IsoP 和 PGE2 水平，在 PND 1 和 21 时，BTBR T+tf/J 小鼠中 15-F2t-IsoP 增加，在 PND 21 和 70 时 BTBR T+tf/J 小鼠中 PGE2 升高。在 PND 21 时，CPF 效果呈性别依赖性，即这两种代谢物主要与雄性小鼠有关。 CPF 治疗还诱导体细胞生长减少，在 PND 21 时达到统计学显着性。这些发现表明，类似自闭症的 BTBR T+tf/J 品系在妊娠期间非常容易受到环境压力的影响。研究结果进一步支持了这样的假设：氧化应激可能是 CPF 和 ASD 等环境神经毒物之间的联系。产后早期氧化应激水平的增加可能会导致与 ASD 相关的特定途径发生延迟和持久的改变，其中 PGE2 信号传导是一个重要的改变。
Autism spectrum disorders (ASD) are emerging as polygenic and multifactorial disorders in which complex interactions between defective genes and early exposure to environmental stressors impact on the correct neurodevelopment and brain processes. Organophosphate insecticides, among which chlorpyrifos (CPF), are widely diffused environmental toxicants associated with neurobehavioral deficits and increased risk of ASD occurrence in children. Oxidative stress and dysregulated immune responses are implicated in both organophosphate neurodevelopmental effects and ASD etiopathogenesis. BTBR T+tf/J mice, a well-studied model of idiopathic autism, show several behavioral and immunological alterations found in ASD children, and we recently showed that CPF gestational exposure strengthened some of these autistic-like traits. In the present study, we aimed at investigating whether the behavioral effects of gestational CPF administration are associated with brain increased oxidative stress and altered lipid mediator profile. Brain levels of F2-isoprostanes (15-F2t-IsoP), as index of in vivo oxidative stress, and prostaglandin E2 (PGE2), a major arachidonic acid metabolite released by immune cells and by specific glutamatergic neuron populations mainly in cortex and hippocampus, were assessed by specific enzyme-immuno assays in brain homogenates from BTBR T+tf/J and C57Bl6/J mice, exposed during gestation to either vehicle or CPF. Measures were performed in mice of both sexes, at different postnatal stages (PNDs 1, 21, and 70). At birth, BTBR T+tf/J mice exhibited higher baseline 15-F2t-IsoP levels as compared to C57Bl6/J mice, suggestive of greater oxidative stress processes. Gestational treatment with CPF-enhanced 15-F2t-IsoP and PGE2 levels in strain- and age-dependent manner, with 15-F2t-IsoP increased in BTBR T+tf/J mice at PNDs 1 and 21, and PGE2 elevated in BTBR T+tf/J mice at PNDs 21 and 70. At PND 21, CPF effects were sex-dependent being the increase of the two metabolites mainly associated with male mice. CPF treatment also induced a reduction of somatic growth, which reached statistical significance at PND 21. These findings indicate that the autistic-like BTBR T+tf/J strain is highly vulnerable to environmental stressors during gestational period. The results further support the hypothesis that oxidative stress might be the link between environmental neurotoxicants such as CPF and ASD. The increased levels of oxidative stress during early postnatal life could result in delayed and long-lasting alterations in specific pathways relevant to ASD, of which PGE2 signaling represents an important one.