Deciphering the toxicity of zearalenone congeners in pigs

玉米赤霉烯酮(ZEA)是一种真菌毒素，由于其模拟内源性雌激素的作用而对猪的繁殖性能产生重大影响，从而扰乱激素的动态平衡。除了雌激素活性外，ZEA还具有其他几种生物效应。在子宫中，这种真菌毒素可能会改变炎症的动态平衡。此外，它还激活了几个外来生物感知受体和相关的生物转化酶，可能导致毒素和药物的肝脏新陈代谢改变。最近的研究表明，在各种谷类饲料中发现的修饰形式的ZEA可能具有雌激素样潜力，甚至可能超过天然真菌毒素。饮食中暴露于改良霉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。这对猪来说似乎很重要，因为猪也接触了其他具有雌激素活性的化合物，包括交链孢霉毒素真菌和大豆中含有的雌激素异黄酮。本研究的目的是研究玉米的毒性和作用机制，以及它们与其他外源物质在猪体内的相互作用。我未来5年的具体目标是：(1)表征六种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的动态平衡的影响；(2)分析ZEA同系物与猪饲料中其他共生的外来雌激素的组合雌激素活性；以及(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)确定一组基因，这些基因将作为体外雌激素刺激猪子宫内膜的指纹。将研究ZEA和五种修饰形式对这些候选基因表达的剂量-效应关系，并相应地建立相对效力因子。此外，我们还将阐明ZEA同系物对猪子宫内膜炎性反应的动态平衡的影响，以及它们与生育力下降的关系。对于目标2，将在与猪饲料有关的剂量范围和混合比例下，研究玉米同系物、交链孢霉毒素和大豆异黄酮类化合物在未成熟母猪子宫内膜外植体上的联合雌激素活性的相互作用。对于目标3，我们将分析ZEA同系物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同系物与由相关肝酶代谢的猪药物的药代动力学相互作用。这项研究提供的数据将有助于监管机构为猪饲料的ZEA污染水平制定更合适的标准。此外，将确定养猪业中与玉米赤霉菌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.