title: Toxicogenomic Screening of Replacements for Di(2-Ethylhexyl) Phthalate (DEHP) Using the Immortalized TM4 Sertoli Cell Line.
abstract: Phthalate plasticizers such as di(2-ethylhexyl) phthalate (DEHP) are being phased out of many consumer products because of their endocrine disrupting properties and their ubiquitous presence in the environment. The concerns raised from the use of phthalates have prompted consumers, government, and industry to find alternative plasticizers that are safe, biodegradable, and have the versatility for multiple commercial applications. We examined the toxicogenomic profile of mono(2-ethylhexyl) phthalate (MEHP, the active metabolite of DEHP), the commercial plasticizer diisononyl cyclohexane-1,2-dicarboxylate (DINCH), and three recently proposed plasticizers: 1,4-butanediol dibenzoate (BDB), dioctyl succinate (DOS), and dioctyl maleate (DOM), using the immortalized TM4 Sertoli cell line. Results of gene expression studies revealed that DOS and BDB clustered with control samples while MEHP, DINCH and DOM were distributed far away from the control-DOS-BDB cluster, as determined by principle component analysis. While no significant changes in gene expression were found after treatment with BDB and DOS, treatment with MEHP, DINCH and DOM resulted in many differentially expressed genes. MEHP upregulated genes downstream of PPAR and targeted pathways of cholesterol biosynthesis without modulating the expression of PPAR's themselves. DOM upregulated genes involved in glutathione stress response, DNA repair, and cholesterol biosynthesis. Treatment with DINCH resulted in altered expression of a large number of genes involved in major signal transduction pathways including ERK/MAPK and Rho signalling. These data suggest DOS and BDB may be safer alternatives to DEHP/MEHP than DOM or the commercial alternative DINCH.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Nardelli
authors.affiliation: Department of Chemical Engineering, McGill University, Montreal, Quebec, Canada.
authors.forename: Hanno C
authors.initials: HC
authors.lastname: Erythropel
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada; Department of Obstetrics and Gynecology, McGill University, Montreal, QC, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Robaire
mesh_terms: D001560:Benzidines / Q000009:adverse effects; D002460:Cell Line; D003509:Cyclohexanecarboxylic Acids / Q000009:adverse effects; D003998:Dicarboxylic Acids / Q000009:adverse effects; D004051:Diethylhexyl Phthalate / Q000009:adverse effects* / Q000031:analogs & derivatives; D052244:Endocrine Disruptors / Q000009:adverse effects; D004781:Environmental Exposure / Q000009:adverse effects; D006801:Humans; D008297:Male; D008298:Maleates / Q000009:adverse effects; D010795:Phthalic Acids / Q000009:adverse effects*; D010968:Plasticizers / Q000009:adverse effects*; D012708:Sertoli Cells / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D043922:Toxicogenetics / Q000379:methods
chemical_list: D001560:Benzidines; D003509:Cyclohexanecarboxylic Acids; D003998:Dicarboxylic Acids; D052244:Endocrine Disruptors; D008298:Maleates; D010795:Phthalic Acids; D010968:Plasticizers; C558012:diisononyl 1,2-cyclohexanedicarboxylic acid; C006770:bis(diazo)benzidine; C032279:phthalic acid; D004051:Diethylhexyl Phthalate; C016599:mono-(2-ethylhexyl)phthalate; C484947:dioctyl maleate