title: In vitro functional screening as a means to identify new plasticizers devoid of reproductive toxicity.
abstract: Plasticizers are indispensable additives providing flexibility and malleability to plastics. Among them, several phthalates, including di (2-ethylhexyl) phthalate (DEHP), have emerged as endocrine disruptors, leading to their restriction in consumer products and creating a need for new, safer plasticizers. The goal of this project was to use in vitro functional screening tools to select novel non-toxic plasticizers suitable for further in vivo evaluation. A panel of novel compounds with satisfactory plasticizer properties and biodegradability were tested, along with several commercial plasticizers, such as diisononyl-cyclohexane-1,2-dicarboxylate (DINCH®). MEHP, the monoester metabolite of DEHP was also included as reference compound. Because phthalates target mainly testicular function, including androgen production and spermatogenesis, we used the mouse MA-10 Leydig and C18-4 spermatogonial cell lines as surrogates to examine cell survival, proliferation, steroidogenesis and mitochondrial integrity. The most promising compounds were further assessed on organ cultures of rat fetal and neonatal testes, corresponding to sensitive developmental windows. Dose-response studies revealed the toxicity of most maleates and fumarates, while identifying several dibenzoate and succinate plasticizers as innocuous on Leydig and germ cells. Interestingly, DINCH®, a plasticizer marketed as a safe alternative to phthalates, exerted a biphasic effect on steroid production in MA-10 and fetal Leydig cells. MEHP was the only plasticizer inducing the formation of multinucleated germ cells (MNG) in organ culture. Overall, organ cultures corroborated the cell line data, identifying one dibenzoate and one succinate as the most promising candidates. The adoption of such collaborative approaches for developing new chemicals should help prevent the development of compounds potentially harmful to human health.
authors.affiliation: The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada H4A 3J1; Department of Medicine, McGill University, Montreal, Quebec, Canada H4A 3J1.
authors.forename: Annie
authors.initials: A
authors.lastname: Boisvert
authors.affiliation: The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada H4A 3J1; Department of Medicine, McGill University, Montreal, Quebec, Canada H4A 3J1.
authors.forename: Steven
authors.initials: S
authors.lastname: Jones
authors.affiliation: The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada H4A 3J1; Department of Medicine, McGill University, Montreal, Quebec, Canada H4A 3J1.
authors.forename: Leeyah
authors.initials: L
authors.lastname: Issop
authors.affiliation: Department of Chemical Engineering, McGill University, Montreal, Quebec, Canada H4A 3J1.
authors.forename: Hanno C
authors.initials: HC
authors.lastname: Erythropel
authors.affiliation: The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada H4A 3J1; Department of Medicine, McGill University, Montreal, Quebec, Canada H4A 3J1; Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada H4A 3J1.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Papadopoulos
authors.affiliation: The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada H4A 3J1; Department of Medicine, McGill University, Montreal, Quebec, Canada H4A 3J1; Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada H4A 3J1. Electronic address: martine.culty@mcgill.ca.
authors.forename: Martine
authors.initials: M
authors.lastname: Culty
mesh_terms: D000818:Animals; D001681:Biological Assay; D002264:Carboxylic Acids / Q000633:toxicity*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D008297:Male; D051379:Mice; D010968:Plasticizers / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D013737:Testis / Q000166:cytology
chemical_list: D002264:Carboxylic Acids; D010968:Plasticizers
keywords: Leydig cells; germ cells; plasticizers; proliferation; steroidogenesis; testis; toxicity