Institut national de la recherche scientifique (INRS) - Centre Eau Terre Environnement, 490 rue de la Couronne, Québec City, QC, G1K 9A9, Canada.
Department of Chemical Engineering, McGill University, 3610 University St, Montreal, QC, H3A 0C5, Canada.
Arch Environ Contam Toxicol. 2021 May;80(4):745-759. doi: 10.1007/s00244-021-00831-5. Epub 2021 Apr 15.
Gestagens are active ingredients in human and veterinary drugs with progestogenic activity. Two gestagens-progesterone (P4), and the synthetic P4 analogue, melengestrol acetate (MGA)-are approved for use in beef cattle agriculture in North America. Both P4 and MGA have been measured in surface water receiving runoff from animal agricultural operations. This project aimed to assess the morphometric and molecular consequences of chronic exposures to P4, MGA, and their mixture during Western clawed frog metamorphosis. Chronic exposure (from embryo to metamorphosis) to MGA (1.7 µg/L) or P4 + MGA (0.22 µg/L P4 + 1.5 µg/L MGA) caused a considerable dysregulation of metamorphic timing, as evidenced by an inhibition of growth, narrower head, and lack of forelimb emergence in all animals. Molecular analysis revealed that chronic exposure to the mixture induced an additive upregulation of neurosteroid-related (GABA receptor subunit α6 (gabra6) and steroid 5-alpha reductase 1 (srd5α1) gene expression in brain tissue. Chronic P4 exposure (0.26 µg/L P4) induced a significant upregulation of the expression hypothalamic-pituitary-gonadal (HPG)-related genes (ipgr, erα) in the gonadal mesonephros complex (GMC). Our data suggest that exposure to P4, MGA, and their mixture induces multiple endocrine responses and adverse effects in larval Western clawed frogs. This study helps to better our understanding of the consequences of chronic gestagen exposure and suggests that the implications and risk of high gestagen use in beef cattle feeding operations may extend to the aquatic environment.
孕激素是具有孕激素活性的人用和兽用药物的有效成分。两种孕激素-孕酮（P4）和合成的 P4 类似物，醋酸美仑孕酮（MGA）-已被批准用于北美的肉牛养殖业。P4 和 MGA 都在接受动物农业作业径流的地表水有所测量。本项目旨在评估慢性暴露于 P4、MGA 及其混合物对西方爪蟾变态期间形态和分子的影响。慢性暴露（从胚胎到变态）于 MGA（1.7µg/L）或 P4+MGA（0.22µg/L P4+1.5µg/L MGA）导致变态时间的严重失调，所有动物的生长抑制、头部变窄和前肢缺失都证明了这一点。分子分析表明，混合物的慢性暴露导致神经甾体相关基因（GABA 受体亚单位α6（gabra6）和类固醇 5-α 还原酶 1（srd5α1））在脑组织中的表达呈相加上调。慢性 P4 暴露（0.26µg/L P4）诱导性腺中下丘脑-垂体-性腺（HPG）相关基因（ipgr、erα）在性腺中肾间叶复合物（GMC）中的表达显著上调。我们的数据表明，P4、MGA 及其混合物的暴露会诱导幼体西方爪蟾的多种内分泌反应和不良反应。这项研究有助于更好地了解慢性孕激素暴露的后果，并表明在肉牛饲养作业中高孕激素使用的影响和风险可能会扩展到水生环境。
