Mathouchanh Mandarin, Lessman Charles A
Department of Biological Sciences, The University of Memphis, Memphis, TN , 38152 , USA.
Fish Physiol Biochem. 2025 May 29;51(3):105. doi: 10.1007/s10695-025-01519-6.
The steroid hormone progesterone (P4) and related compounds called progestogens are well known for their effects on the reproductive system. However, their physiological roles outside reproduction are less understood. Additionally, there is limited information on the toxicological repercussions of environmental exposure to exogenous progestogens and how such exposure might impact the development and survival of animals living in contaminated habitats. Two progesterone-based neurosteroids, allopregnanolone and tetrahydrodeoxycorticosterone (THDOC), are known to enhance γ-aminobutyric acid type A (GABA) receptor activity, inducing neuronal hyperpolarization. In this study, locomotor parameters in zebrafish embryos and larvae were used as endpoints to assess the inhibitory effects of pregnane neurosteroids. Specifically, spontaneous tail coiling in embryos at 24 h post-fertilization (hpf) and swimming activity in larvae aged 120-168 hpf were evaluated. Motility assays in embryos showed that P4 increased spontaneous tail coiling, whereas larvae exhibited an anesthetic-like loss of motility. This effect was both age- and dose-dependent for P4, deoxycorticosterone (DOC), 5α-dihydroprogesterone, and the membrane progesterone receptor agonist, ORG-OD-02-0, but not for other steroids tested. Removal of the steroids after the onset of anesthesia led to recovery of motility in larvae, suggesting that the observed effects are not due to a non-specific toxicity. Our results suggest that P4 targets the mPR, which acts in association with the GABA receptor to mediate the loss of locomotor behavior. This study provides further insight into how neuroactive compounds can affect locomotor behaviors during early developmental stages in nonmammalian species.
类固醇激素孕酮（P4）以及被称为孕激素的相关化合物，因其对生殖系统的作用而广为人知。然而，它们在生殖系统之外的生理作用却鲜为人知。此外，关于环境暴露于外源性孕激素的毒理学影响以及这种暴露如何影响生活在受污染栖息地的动物的发育和生存的信息有限。已知两种基于孕酮的神经甾体，别孕烷醇酮和四氢脱氧皮质酮（THDOC），可增强γ-氨基丁酸A型（GABA）受体活性，诱导神经元超极化。在本研究中，斑马鱼胚胎和幼体的运动参数被用作评估孕烷神经甾体抑制作用的终点指标。具体而言，评估了受精后24小时（hpf）胚胎的自发尾部卷曲以及120 - 168 hpf幼体的游泳活动。胚胎运动分析表明，P4增加了自发尾部卷曲，而幼体则表现出类似麻醉的运动能力丧失。P4、脱氧皮质酮（DOC）、5α-二氢孕酮以及膜孕酮受体激动剂ORG - OD - 02 - 0的这种作用具有年龄和剂量依赖性，但其他测试的类固醇则不然。麻醉开始后去除类固醇会导致幼体运动能力恢复，这表明观察到的效应并非由于非特异性毒性。我们的结果表明，P4靶向mPR，mPR与GABA受体协同作用以介导运动行为的丧失。这项研究进一步深入了解了神经活性化合物如何在非哺乳动物物种的早期发育阶段影响运动行为。
