Mohammad Alfatah, Jin Huei Wong, Kiat Whye Kong, Felix Utama, Shawn Hoon, Prakash Arumugam, Chemical-genetic interaction landscape of mono-(2-ethylhexyl)-phthalate using chemogenomic profiling in yeast, Chemosphere, Volume 228, 2019, Pages 219-231, ISSN 0045-6535, https://doi.org/10.1016/j.chemosphere.2019.04.100.
Integration of chemical-genetic interaction data with biological functions provides a mechanistic understanding of how toxic compounds affect cells. Mono-(2-ethylhexyl)-phthalate (MEHP) is an active metabolite of di-(2-ethylhexyl)-phthalate (DEHP), a commonly used plasticizer. MEHP adversely affects human health causing hepatotoxicity and reproductive toxicity. How MEHP affects cellular physiology is not fully understood. We utilized a genome-wide competitive fitness-based assay called 'chemogenomic profiling' to determine the genetic interaction map of MEHP in Saccharomyces cerevisiae. Gene Ontology enrichment analysis of 218 genes that provide resistance to MEHP indicated that MEHP affects seven cellular processes namely: (1) cellular amino acid biosynthetic process, (2) sterol biosynthetic process, (3) cellular transport, (4) transcriptional and translational regulation, (5) protein glycosylation, (6) cytokinesis and cell morphogenesis and (7) ionic homeostasis. We show that MEHP protects yeast cells from membrane perturbing agents such as amphotericin B, dihydrosphingosine and phytosphingosine. Moreover, we also demonstrate that MEHP compromises the integrity of the yeast plasma membrane and cell wall. Our work provides a basis for further investigation of MEHP toxicity in humans.
We are grateful to the funding provided by the Bioinformatics Institute (BII), Biomedical Research Council (BMRC) - Economic Development Board (EDB) Industry Fund (1AF311017G) and Agency for Science, Technology and Research (A*STAR) Singapore. We thank Dr Lit-Hsin Loo for providing us a DEHP and Dr Melvin Andersen for suggesting us to investigate the mode-of-action of MEHP by chemogenomic profiling.