Deciphering the toxicity of zearalenone congeners in pigs

破译玉米赤霉烯酮同系物对猪的毒性

• 批准号: RGPIN-2021-02997
• 负责人: ALASSANEKPEMBI, Imourana
• 金额: $ 2.04万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746061
• 关键词: Deciphering; toxicity; zearalenone; congeners; pigs

Zearalenone (ZEA) is a mycotoxin that has a significant impact on reproductive performance in pigs due to its action mimicking endogenous estrogens, which disturbs hormonal homeostasis. Apart from estrogenic activity, ZEA exerts several other biological effects. In the uterus, this mycotoxin may alter the inflammatory homeostasis. Moreover, it activates several xenobiotic-sensing receptors and related biotransformation enzymes, possibly leading to altered liver metabolism of toxins and pharmaceuticals. Recent studies indicate that modified forms of ZEA found in a variety of cereal-based feedstuffs may possess estrogenic potential that could even exceed that of the native mycotoxin. A further neglected aspect of dietary exposure to modified mycotoxins relates to potential combinatory effects with other contaminants. This appears important in pigs that are also exposed to other compounds exerting estrogenic activity, including Alternaria mycotoxins fungi, and estrogenic isoflavones contained in soy. The aim of my research is to characterize the toxicity and mechanisms of action of ZEA congeners, and their interactions with other xenobiotics in pigs. My specific goals for the next 5 years are: (1) characterize the estrogenicity potencies of six ZEA congeners, and elucidate their effect on the homeostasis of the inflammatory response in pig endometrium; (2) analyse the combined estrogenicity of the ZEA congeners with the other co-occurring xenoestrogens in pig feed; and (3) characterize the effects of ZEA congeners on the metabolism of the main drugs used in the pig industry. For Objective 1, we will identify, by high-throughput transcriptomics (RNAseq) a set of genes that will serve as fingerprint for ex vivo estrogenic stimulation of pig endometrium. The dose-effect relationships of ZEA and five modified forms on the expression of those candidate genes will be investigated, and relative potency factors will be established accordingly. Besides, we will elucidate the effects of ZEA congeners on the homeostasis of the inflammatory response in pig endometrium, and their connexion with reduced fertility. For Objective 2, the interactions for the combined estrogenicity of ZEA congeners, Alternaria mycotoxins and soybean isoflavones will be investigated on immature gilt endometrium explants, at dose ranges and ratio of mixtures that are relevant to pig feed. For Objective 3, we will analyse the effects of ZEA congeners on the xenobiotic-sensing transcription factors and the expression of related drug metabolism enzymes. Then we will characterize in vitro the pharmacokinetic interactions of ZEA congeners with pig drugs that are metabolized by the relevant liver enzymes. Data provided by this research will help regulation agencies to set more appropriate standards for ZEA contamination levels for pigs feed. Moreover, drugs in the pig industry whose interaction with ZEA congeners may result in treatment failure or toxic responses will be identified.

玉米赤霉烯酮（ZEA）是一种真菌毒素，由于其作用类似于内源性雌激素，扰乱激素的稳态，对猪的繁殖性能有显著影响。除了雌激素活性，ZEA还发挥其他几种生物学作用。在子宫中，这种霉菌毒素可能改变炎症的稳态。此外，它激活几种异生物质感应受体和相关的生物转化酶，可能导致改变肝脏代谢的毒素和药物。最近的研究表明，在各种谷物饲料中发现的ZEA的修饰形式可能具有雌激素潜力，甚至可能超过天然真菌毒素。从饮食中接触改性真菌毒素的另一个被忽视的方面涉及与其他污染物的潜在组合效应。这对于暴露于其他具有雌激素活性的化合物（包括链格孢霉菌毒素真菌和大豆中含有的雌激素类黄酮）的猪来说似乎很重要。本研究的目的是描述ZEA同系物的毒性和作用机制，以及它们与其他外源性物质在猪体内的相互作用。本研究的主要目标是：（1）研究6种ZEA同源物的雌激素活性及其对猪子宫内膜炎性反应的影响;（2）研究ZEA同源物与其他外源性雌激素在猪饲料中的联合雌激素活性;以及（3）表征ZEA同系物对养猪业中使用的主要药物代谢的影响。对于目标1，我们将通过高通量转录组学（RNAseq）鉴定一组基因，这些基因将作为猪子宫内膜离体雌激素刺激的指纹图谱。将研究ZEA及其5种修饰形式对这些候选基因表达的量效关系，并据此建立相对效力因子。此外，我们将阐明ZEA同源物对猪子宫内膜炎症反应的稳态的影响，以及它们与生育力下降的关系。 对于目标2，将在与猪饲料相关的剂量范围和混合物比例下，在未成熟后备母猪子宫内膜外植体上研究ZEA同源物、链格孢霉菌毒素和大豆异黄酮的联合雌激素活性的相互作用。目标3：分析ZEA同源物对异生物素敏感转录因子和相关药物代谢酶表达的影响。然后，我们将在体外表征ZEA同系物与猪药物的药代动力学相互作用，这些药物通过相关的肝酶代谢。 本研究提供的数据将有助于监管机构制定更合适的猪饲料ZEA污染水平标准。此外，将确定养猪业中与ZEA同系物相互作用可能导致治疗失败或毒性反应的药物。