Effect of developmental NMDAR antagonism with CGP 39551 on aspartame-induced hypothalamic and adrenal gene expression.
Effect of developmental NMDAR antagonism with CGP 39551 on aspartame-induced hypothalamic and adrenal gene expression.
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DOI：
10.1371/journal.pone.0194416
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Al-Mohanna FA
中科院分区：
文献类型：
--
作者：
Collison KS;Inglis A;Shibin S;Saleh S;Andres B;Ubungen R;Thiam J;Mata P;Al-Mohanna FA
阿斯巴甜（L-乙酰基苯丙氨酸甲酯）是一种非营养性甜味剂（NNS），被批准用于一般公众（包括成人和儿童、孕妇和哺乳期母亲）消费的6000多种膳食产品和药物。然而，最近的一项前瞻性研究报告称，母亲在怀孕期间每天饮用NNS甜味饮料的1岁儿童超重的风险增加了一倍。我们之前已经证明，从子宫内开始的长期阿斯巴甜（ASP）暴露可能会对成年肥胖状态、葡萄糖代谢以及行为和空间认知方面产生不利影响，并且这可以通过发育N-甲基-D-天冬氨酸受体（NMDAR）阻断来调节竞争性拮抗剂CGP 39551（CGP）。由于葡萄糖稳态和行为和运动的某些方面部分地由富含NMDAR的下丘脑调节，下丘脑是下丘脑-垂体-肾上腺-（HPA）轴的一部分，因此我们选择使用Affytron微阵列分析来检查下丘脑和肾上腺基因表达的变化，以响应在存在或不存在与CGP的发育NMDAR拮抗作用的情况下ASP暴露。使用2因素方差分析，我们确定了189 ASP响应差异表达基因（DEG）在成年男性下丘脑和2188肾上腺，和进一步的23下丘脑和232肾上腺基因显着调节与CGP单独的发育治疗。ASP暴露强烈升高了参与下丘脑神经类固醇生成的基因网络以及细胞应激和炎症基因的表达，这与先前关于庆大霉素诱导的CNS应激和氧化损伤的报道一致。这些基因在具有CGP拮抗作用的ASP小鼠中没有差异表达。在ASP暴露小鼠的肾上腺中，GABA和谷氨酸受体亚单位基因是其中最高度上调的。单独的发育性NMDAR拮抗作用对成年期基因表达的影响较小，主要影响下丘脑神经发生和肾上腺类固醇代谢。ASP + CGP联合治疗主要上调肾上腺药物和胆固醇代谢相关基因。ASP暴露增加了参与下丘脑神经类固醇生成和肾上腺儿茶酚胺合成的基因的功能网络的表达，这些表达模式在ASP暴露的小鼠中不存在，具有发育NMDAR拮抗作用。
Aspartame (L-aspartyl phenylalanine methyl ester) is a non-nutritive sweetener (NNS) approved for use in more than 6000 dietary products and pharmaceuticals consumed by the general public including adults and children, pregnant and nursing mothers. However a recent prospective study reported a doubling of the risk of being overweight amongst 1-year old children whose mothers consumed NNS-sweetened beverages daily during pregnancy. We have previously shown that chronic aspartame (ASP) exposure commencing in utero may detrimentally affect adulthood adiposity status, glucose metabolism and aspects of behavior and spatial cognition, and that this can be modulated by developmental N-methyl-D-aspartate receptor (NMDAR) blockade with the competitive antagonist CGP 39551 (CGP). Since glucose homeostasis and certain aspects of behavior and locomotion are regulated in part by the NMDAR-rich hypothalamus, which is part of the hypothalamic-pituitary-adrenal- (HPA) axis, we have elected to examine changes in hypothalamic and adrenal gene expression in response to ASP exposure in the presence or absence of developmental NMDAR antagonism with CGP, using Affymetrix microarray analysis. Using 2-factor ANOVA we identified 189 ASP-responsive differentially expressed genes (DEGs) in the adult male hypothalamus and 2188 in the adrenals, and a further 23 hypothalamic and 232 adrenal genes significantly regulated by developmental treatment with CGP alone. ASP exposure robustly elevated the expression of a network of genes involved in hypothalamic neurosteroidogenesis, together with cell stress and inflammatory genes, consistent with previous reports of aspartame-induced CNS stress and oxidative damage. These genes were not differentially expressed in ASP mice with CGP antagonism. In the adrenal glands of ASP-exposed mice, GABA and Glutamate receptor subunit genes were amongst those most highly upregulated. Developmental NMDAR antagonism alone had less effect on adulthood gene expression and affected mainly hypothalamic neurogenesis and adrenal steroid metabolism. Combined ASP + CGP treatment mainly upregulated genes involved in adrenal drug and cholesterol metabolism. ASP exposure increased the expression of functional networks of genes involved in hypothalamic neurosteroidogenesis and adrenal catecholamine synthesis, patterns of expression which were not present in ASP-exposed mice with developmental NMDAR antagonism.
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影响因子：
3.8
作者：
Cho, SB;McDonald, JD
通讯作者：
McDonald, JD
影响因子：
2.9
作者：
Brooks, WJ;Weeks, ACW;Petit, TL
通讯作者：
Petit, TL
影响因子：
4.4
作者：
Collison, Kate S.;Zaidi, Marya Z.;Al-Mohanna, Futwan A.
通讯作者：
Al-Mohanna, Futwan A.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
4.2
作者：
Arce, C;del Campo, AB;González, MP
通讯作者：
González, MP