<br>ERβ 激活通过 TPH2/5-HT 通路改善壬基酚诱导的抑郁症和神经递质分泌干扰,Ecotoxicology and Environmental Safety

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ERβ 激活通过 TPH2/5-HT 通路改善壬基酚诱导的抑郁症和神经递质分泌干扰
Ecotoxicology and Environmental Safety ( IF 6.2 ) Pub Date : 2024-06-08 , DOI: 10.1016/j.ecoenv.2024.116521
Jie Yu ₁ , Yujie Zhang ₁ , Hao Yao ₁ , Ziping Zhang ₂ , Xiao Yang ₁ , Wei Zhu ₁ , Jie Xu ₁

Affiliation

本研究的目的是探讨雌激素受体β （ERβ）在壬基酚（NP）诱导的大鼠抑郁样行为中的作用及其对 TPH2/5-HT 通路调节的影响。实验将大鼠嗜碱性白血病细胞（RBL-2H3）细胞分为 4 组：空白组、NP 组（20 μM）、ERβ 激动剂组（0.01 μM）和 NP+ERβ 激动剂组（20 μM+0.01 μM）。实验将 72 只成年雄性 Sprague-Dawley 大鼠随机分为以下 6 组：对照组，NP （40 mg/kg）组，ERβ 激动剂（2 mg/kg，二芳基丙腈（DPN））组，ERβ 抑制剂（0.1 mg/kg，4-（2-苯基-5,7-双（三氟甲基）吡唑并[1,5-]嘧啶-3-基）苯酚（PHTPP））组，NP+ERβ 激动剂（40 mg/kg NP + 2 mg/kg DPN）组，和 NP+ERβ 抑制剂（40 mg/kg NP + 0.1 mg/kg PHTPP）组，每组 12 只大鼠。药物组每只大鼠通过管饲法给予 NP 和/或接受单次腹腔注射 DPN 2 mg/kg 或 PHTPP 0.1 mg/kg。和，NP 组均显示 ERβ 、色氨酸羟化酶（TPH1）和色氨酸羟化酶-2 （TPH2）基因和蛋白的表达水平降低，DA 、 NE 和 5-羟色氨酸（5-HT）神经递质水平降低。RBL-2H3 细胞表现出细胞收缩的迹象，细胞呈圆形，悬浮液增加，细胞排列更松散。ERβ 激动剂刺激的有效性在 RBL-2H3 细胞中表现出超过 60% 的增加。ERβ 激动剂的应用导致上述改变的缓解。ERβ 激动剂激活 TPH2/5-HT 信号通路。与对照组相比，NP 组脑组织中 NP 含量显著增加。大鼠进食潜伏期较长，进食量较低，大鼠行为实验中不动时间延长。NP 组 ERβ 、 TPH1 、 TPH2 、 5-HT 和 5-HITT 蛋白表达水平降低，提示 NP 诱导的抑郁样行为以及血清激素和单胺类神经递质分泌紊乱。在 NP 组中，中缝核呈细长核，呈深紫蓝色、核萎缩、移位和苍白的细胞质。ERβ 可能通过激活 TPH2/5-HT 信号通路改善 NP 诱导的抑郁样行为，以及血清激素和单胺类神经递质的分泌障碍。

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ERβ activation improves nonylphenol-induced depression and neurotransmitter secretion disruption via the TPH2/5-HT pathway

The aim of this study is to investigate the role of estrogen receptor β (ERβ) in nonylphenol (NP) - induced depression - like behavior in rats and its impact on the regulation of the TPH2/5-HT pathway. In the experiment, rat basophilic leukaemia cells (RBL-2H3) cells were divided into the four groups: blank group, NP group (20 μM), ERβ agonist group (0.01 μM), and NP＋ERβ agonist group (20 μM＋0.01 μM). For the experiment, 72 adult male Sprague-Dawley rats were randomly divided into following six groups: the Control, NP (40 mg/kg) group, ERβ agonist (2 mg/kg, Diarylpropionitrile (DPN)) group, ERβ inhibitor (0.1 mg/kg, 4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-]pyrimidin-3-yl) phenol (PHTPP)) group, NP+ERβ agonist (40 mg/kg NP ＋ 2 mg/kg DPN) group, and NP+ERβ inhibitor (40 mg/kg NP + 0.1 mg/kg PHTPP) group, with 12 rats in each group. Each rat in drug group were given NP by gavage and/or received a single intraperitoneal injection of DPN 2 mg/kg or PHTPP 0.1 mg/kg. Both and , NP group showed a decrease in the expression levels of ERβ, tryptophan hydroxylase (TPH1), and tryptophan hydroxylase-2 (TPH2) genes and proteins, and reduced levels of DA, NE, and 5-hydroxytryptophan (5-HT) neurotransmitters. RBL-2H3 cells showed signs of cell shrinkage, with rounded cells, increased suspension and more loosely arranged cells. The effectiveness of the ERβ agonist stimulation exhibited an increase exceeding 60% in RBL-2H3 cells. The application of ERβ agonist resulted in an alleviation the aforementioned alterations. ERβ agonist activated the TPH2/5-HT signaling pathways. Compared to the control group, the NP content in the brain tissue of the NP group was significantly increased. The latency to eat for the rats was longer and the amount of food consumed was lower, and the rats had prolonged immobility time in the behavioral experiment of rats. The expression levels of ERβ, TPH1, TPH2, 5-HT and 5-HITT proteins were decreased in the NP group, suggesting NP-induced depression-like behaviours as well as disturbances in the secretion of serum hormones and monoamine neurotransmitters. In the NP group, the midline raphe nucleus showed an elongated nucleus with a dark purplish-blue colour, nuclear atrophy, displacement and pale cytoplasm. ERβ might ameliorate NP-induced depression-like behaviors, and secretion disorders of serum hormones and monoamine neurotransmitters via activating TPH2/5-HT signaling pathways.

更新日期：2024-06-08

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