Deciphering the toxicity of zearalenone congeners in pigs

点击翻译按钮获取中文摘要

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.