Bioinformatics Institute, 30 Biopolis Street, Singapore, 138671, Singapore.
Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, Singapore, 138602, Singapore.
Sci Rep. 2022 Jun 17;12(1):10237. doi: 10.1038/s41598-022-14284-w.
Phthalates are ubiquitously used as plasticizers in various consumer care products. Diethyl phthalate (DEP), one of the main phthalates, elicits developmental and reproductive toxicities but the underlying mechanisms are not fully understood. Chemogenomic profiling of DEP in S. cerevisiae revealed that two transcription factors Stp1 and Dal81 involved in the Ssy1-Ptr5-Ssy5 (SPS) amino acid-sensing pathway provide resistance to DEP. Growth inhibition of yeast cells by DEP was stronger in poor nitrogen medium in comparison to nitrogen-rich medium. Addition of amino acids to nitrogen-poor medium suppressed DEP toxicity. Catabolism of amino acids via the Ehrlich pathway is required for suppressing DEP toxicity. Targeted metabolite analyses showed that DEP treatment alters the amino acid profile of yeast cells. We propose that DEP inhibits the growth of yeast cells by affecting nitrogen metabolism and discuss the implications of our findings on DEP-mediated toxic effects in humans.
邻苯二甲酸酯作为各种消费护理产品中的增塑剂被广泛使用。邻苯二甲酸二乙酯 (DEP) 是主要的邻苯二甲酸酯之一，会引起发育和生殖毒性，但其中的机制尚不完全清楚。在酿酒酵母中对 DEP 的化学生物基因组学分析显示，两个转录因子 Stp1 和 Dal81 参与 Ssy1-Ptr5-Ssy5（SPS）氨基酸感应途径，为 DEP 提供了抗性。与富氮培养基相比，DEP 对酵母细胞在贫氮培养基中的生长抑制作用更强。向贫氮培养基中添加氨基酸可以抑制 DEP 的毒性。通过 Ehrlich 途径分解氨基酸对于抑制 DEP 毒性是必需的。靶向代谢物分析表明，DEP 处理改变了酵母细胞的氨基酸谱。我们提出 DEP 通过影响氮代谢来抑制酵母细胞的生长，并讨论了我们的发现对人类中 DEP 介导的毒性影响的意义。
