核激素受体控制人类胎儿神经发育的基本过程:内分泌干扰评估的基础
Katharina Koch1, Kevin Schlüppmann2, Saskia Hüsken2
1IUF - Leibniz Research Institute for Environmental Medicine, Duesseldorf, Germany; DNTOX GmbH, Duesseldorf, Germany.
Environment international
|March 27, 2025
概括
内分泌干扰化学物质 (EDC) 对人类大脑发育构成风险. 这项研究扩展了EDC风险评估,通过使用神经圈试验评估激素受体对神经发育的影响,揭示了特定物种的影响.
科学领域:
- 神经科学是一个神经科学.
- 毒理学 毒理学 毒理学
- 内分泌学 在内分泌学.
背景情况:
- 内分泌干扰化学物质 (EDC) 对人类大脑发育构成风险,但目前的风险评估有限.
- 现有的评估主要集中在雌激素,雌激素和甲状腺激素通路上,忽视了发育中的大脑中的其他关键激素受体.
- 这种监督妨碍了对内分泌干扰中介发育神经毒性 (ED-DNT) 的化学品的准确评估.
研究的目的:
- 定义用于评估ED-DNT的神经圈试验的内分泌相关适用性领域.
- 评估14种激素受体对人类和老鼠神经前体细胞 (NPC) 中关键神经发育过程 (KNDP) 的影响和特异性.
- 用转录学和化学暴露来研究物种和性别特异性反应和潜在机制.
主要方法:
- 利用神经圈测试,一种用于发育神经毒性 (DNT) 测试的体外方法.
- 评估了14种激素受体对7种KNDP的影响,包括细胞增殖,迁移,神经元外生和分化.
- 采用RNA测序和agonist/antagonist共同暴露以获得机械洞察力和特异性确认.
主要成果:
- 大多数测试的激素受体激素剂在生理学上相关的度调节KNDPs.
- 现型效应是特定的,受体对抗剂抵消激素诱导的变化证实了这一点.
- 转录组学揭示了显著的受体交叉声和保留的发育途径 (例如,Notch,Wnt) 的参与.
- 在受激素受体调节的KNDP中,人类和老鼠NPC之间观察到有限的一致性,突出了物种差异.
结论:
- 这项研究为人类胎儿NPCs的细胞和分子激素作用提供了新的见解.
- 在神经发育对激素受体激活反应中表现出显著的物种差异.
- 验证了神经圈测试对检测内分泌作用机制的实用性,支持其在基于人类的ED-DNT风险评估中的应用.
相关概念视频
Neurulation
Neurulation is the embryological process which forms the precursors of the central nervous system and occurs after gastrulation has established the three primary cell layers of the embryo: ectoderm, mesoderm, and endoderm. In humans, the majority of this system is formed via primary neurulation, in which the central portion of the ectoderm—originally appearing as a flat sheet of cells—folds upwards and inwards, sealing off to form a hollow neural tube. As development proceeds, the anterior...
Teratogenicity
The ability of a drug to produce structural deformations and functional abnormalities in the developing embryo or the fetus is called teratogenicity, and the drug producing this effect is known as a teratogen. Teratogenic effects include stillbirth, miscarriage, intrauterine growth restriction, and neurocognitive delay. A teratogen may affect the embryo at different stages of development, which is important in determining the type and extent of the damage. During blastocyst formation, the early...
Signal Transduction: Overview
Cells respond to many types of information, often through receptor proteins positioned on the membrane. They respond to chemical signals, such as hormones, neurotransmitters, and other signaling molecules, initiating a series of molecular reactions to produce an appropriate response. This is called signal transduction. Cells also coordinate different responses elicited by the same signaling molecule via mediators, allowing molecular cross-talk.
Typically, signal transduction involves three...
Typically, signal transduction involves three...
Transducer Mechanism: Nuclear Receptors
Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
Target Cell Response to Hormones
Hormones intricately bind to receptors on the surface or within target cells, initiating a cascade of cellular responses.
Notably, the cellular response can be regulated by altering the number of receptors expressed in the cell. For example, prolonged exposure to elevated hormone levels results in a gradual decline or down-regulation in the number of receptors for that specific hormone on the cell surface. Conversely, in response to low hormone levels, cells may use up-regulation, producing an...
Notably, the cellular response can be regulated by altering the number of receptors expressed in the cell. For example, prolonged exposure to elevated hormone levels results in a gradual decline or down-regulation in the number of receptors for that specific hormone on the cell surface. Conversely, in response to low hormone levels, cells may use up-regulation, producing an...
Gonadal and Placental Hormones
The gonads, namely the testes in males and the ovaries in females, are pivotal in producing gonadal hormones that orchestrate the intricate processes of sexual development and reproduction.
In males, testosterone is the primary gonadal androgen. It plays a central role in the maturation of male reproductive organs — the penis and testes. Additionally, testosterone is instrumental in the development of secondary sexual characteristics — a deep voice as well as facial and pubic hair growth — and...
In males, testosterone is the primary gonadal androgen. It plays a central role in the maturation of male reproductive organs — the penis and testes. Additionally, testosterone is instrumental in the development of secondary sexual characteristics — a deep voice as well as facial and pubic hair growth — and...


