Deciphering the toxicity of zearalenone congeners in pigs

玉米赤霉烯酮（ZEA）是一种真菌毒素，对猪的繁殖性能有重大影响，因为它的作用类似内源性雌激素，会扰乱激素稳态。除了雌激素活性外，ZEA还具有其他几种生物学效应。在子宫内，这种霉菌毒素可能改变炎症稳态。此外，它激活了几种异种生物感应受体和相关的生物转化酶，可能导致肝脏毒素和药物代谢的改变。最近的研究表明，在各种谷物基饲料中发现的改性形式的ZEA可能具有雌激素潜力，甚至可能超过天然霉菌毒素。膳食暴露于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。这对猪来说很重要，因为猪也暴露于其他具有雌激素活性的化合物，包括互交菌真菌毒素和大豆中含有的雌激素异黄酮。我的研究目的是表征ZEA同系物的毒性和作用机制，以及它们与猪体内其他外源药物的相互作用。我未来5年的具体目标是：(1)表征6种ZEA同系物的雌激素活性，并阐明它们对猪子宫内膜炎症反应稳态的影响；(2)分析ZEA同系物与猪饲料中其他异种雌激素的联合雌激素性；(3)表征ZEA同系物对养猪业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，这些基因将作为体外雌激素刺激猪子宫内膜的指纹。研究ZEA及其5种修饰形式对候选基因表达的量效关系，并建立相对效价因子。此外，我们将阐明ZEA同系物对猪子宫内膜炎症反应稳态的影响，以及它们与生育能力下降的关系。在目标2中，我们将在与猪饲料相关的剂量范围和混合比例下，研究ZEA同系物、Alternaria真菌毒素和大豆异黄酮在未成熟的后备母猪子宫内膜外植体上联合雌激素的相互作用。在目标3中，我们将分析ZEA同源基因对外源感应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同系物与被相关肝酶代谢的猪药物的药代动力学相互作用。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。

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.