Abstract：
Zearalenone (ZEN) is a mycoestrogen produced by Fusarium fungi contaminating cereals and in grain-based products threatening human and animal health due to its endocrine disrupting effects. Germane to the mechanisms of action, ZEN may activate the estrogen receptors and inhibit the estrogens-producing enzyme aromatase (CYP19A1). Both show single nucleotide variants (SNVs) among humans associated with a diverse susceptibility of being activated or inhibited. These variations might modify the endocrine disrupting action of ZEN, requiring dedicated studies to improve its toxicological understanding. This work focused on human aromatase investigating via 3D molecular modelling whether some of the SNVs reported so far (n = 434) may affect the inhibitory potential of ZEN. It has been also calculated the inhibition capability of α-zearalenol, the most prominent and estrogenically potent phase I metabolite of ZEN, toward those aromatase variants with an expected diverse sensitivity of being inhibited by ZEN. The study: i) described SNVs likely associated with a different susceptibility to ZEN and α-zearalenol inhibition - like T310S that is likely more susceptible to inhibition, or D309G and S478F that are possibly inactive variants; ii) proofed the possible existence of inter-individual susceptibility to ZEN; iii) prioritized aromatase variants for future investigations toward a better comprehension of ZEN xenoestrogenicity at an individual level.
摘要：
玉米赤霉烯酮是由镰刀菌真菌污染谷物和谷物产品产生的一种雌激素，由于其内分泌干扰作用而威胁人类和动物的健康。德国的行动机制，玉米赤霉烯酮可以激活雌激素受体并抑制雌激素产生酶芳香化酶（CYP19A1）。两者均显示人类中的单核苷酸变体(SNV)与被激活或抑制的不同易感性相关。这些变化可能会改变玉米赤霉烯酮的内分泌干扰作用，需要专门的研究，以提高其毒理学的理解。这项工作集中在通过3D分子建模研究人类芳香化酶，迄今为止报道的某些变体（n=434）是否会影响玉米赤霉烯酮的抑制潜力。还计算了α-玉米赤霉烯醇的抑制能力，玉米赤霉烯酮的最突出和雌激素有效的I相代谢产物，针对那些预期被ZEN抑制的不同敏感性的芳香化酶变体。该研究：i）描述了SNV可能与玉米赤霉烯酮和α-玉米赤霉烯醇抑制的不同易感性相关-像T310S一样，可能更容易受到抑制，或D309G和S478F可能是无活性的变体；ii）证明可能存在个体间对玉米赤霉烯酮的易感性；iii）优先考虑芳香化酶变体，以便将来在个体水平上更好地理解ZEN异种雌激素性。
