title: Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats.
abstract: N,N-dimethyl-p-toluidine (DMPT), an accelerant for methyl methacrylate monomers in medical devices, was a liver carcinogen in male and female F344/N rats and B6C3F1 mice in a 2-year oral exposure study. p-Toluidine, a structurally related chemical, was a liver carcinogen in mice but not in rats in an 18-month feed exposure study. In this current study, liver transcriptomic data were used to characterize mechanisms in DMPT and p-toluidine liver toxicity and for conducting benchmark dose (BMD) analysis. Male F344/N rats were exposed orally to DMPT or p-toluidine (0, 1, 6, 20, 60 or 120 mg/kg/day) for 5 days. The liver was examined for lesions and transcriptomic alterations. Both chemicals caused mild hepatic toxicity at 60 and 120 mg/kg and dose-related transcriptomic alterations in the liver. There were 511 liver transcripts differentially expressed for DMPT and 354 for p-toluidine at 120 mg/kg/day (false discovery rate threshold of 5 %). The liver transcriptomic alterations were characteristic of an anti-oxidative damage response (activation of the Nrf2 pathway) and hepatic toxicity. The top cellular processes in gene ontology (GO) categories altered in livers exposed to DMPT or p-toluidine were used for BMD calculations. The lower confidence bound benchmark doses for these chemicals were 2 mg/kg/day for DMPT and 7 mg/kg/day for p-toluidine. These studies show the promise of using 5-day target organ transcriptomic data to identify chemical-induced molecular changes that can serve as markers for preliminary toxicity risk assessment.
authors.affiliation: Toxicology Branch, National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, NC, 27709, USA. dunnickj@niehs.nih.gov.
authors.forename: June K
authors.initials: JK
authors.lastname: Dunnick
authors.affiliation: Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, NC, 27709, USA.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Shockley
authors.affiliation: NTP Laboratory, National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, NC, 27709, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Morgan
authors.affiliation: Experimental Pathology Laboratories, Inc., National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, NC, 27709, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Brix
authors.affiliation: Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, NC, 27709, USA.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Travlos
authors.affiliation: Molecular Genomics Core, National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, NC, 27709, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Gerrish
authors.affiliation: National Cancer Institute at NIEHS, National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, NC, 27709, USA.
authors.forename: J
authors.initials: J
authors.lastname: Michael Sanders
authors.affiliation: Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, NC, 27709, USA.
authors.forename: T V
authors.initials: TV
authors.lastname: Ton
authors.affiliation: Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, NC, 27709, USA.
authors.forename: Arun R
authors.initials: AR
authors.lastname: Pandiri
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D018570:Risk Assessment / Q000379:methods; D014052:Toluidines / Q000008:administration & dosage / Q000633:toxicity*; D059467:Transcriptome / Q000187:drug effects
chemical_list: D002273:Carcinogens; D014052:Toluidines; C029370:4-toluidine; C015835:dimethyl-4-toluidine
keywords: Liver toxicity; Molecular markers; N,N-dimethyl-p-toluidine; p-Toluidine