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Arch Toxicol. 2017 Apr;91(4):1685-1696. doi: 10.1007/s00204-016-1831-7. Epub 2016 Sep 16.

Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats.

Author information

1
Toxicology Branch, National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, NC, 27709, USA. dunnickj@niehs.nih.gov.
2
Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, NC, 27709, USA.
3
NTP Laboratory, National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, NC, 27709, USA.
4
Experimental Pathology Laboratories, Inc., National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, NC, 27709, USA.
5
Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, NC, 27709, USA.
6
Molecular Genomics Core, National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, NC, 27709, USA.
7
National Cancer Institute at NIEHS, National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, NC, 27709, USA.

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.

KEYWORDS:

Liver toxicity; Molecular markers; N,N-dimethyl-p-toluidine; p-Toluidine

PMID:
27638505
PMCID:
PMC5364093
DOI:
10.1007/s00204-016-1831-7
[Indexed for MEDLINE]
Free PMC Article

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