Molecular Changes in the Nasal Cavity after <i>N, N</i>-dimethyl-p-toluidine Exposure

Dunnick, June K.; Merrick, B. Alex; Brix, Amy E.; Morgan, Daniel L.; Gerrish, Kevin; Wang, Yu; Flake, Gordon P.; Foley, Julie F.; Shockley, Keith R.

doi:10.1177/0192623316637708

Cited by 4 publications

(2 citation statements)

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“…Nrf2 antioxidant responses occur after exposure to other liver toxins including aflatoxin (Kensler et al 2014; Merrick et al 2012; Singh et al 2015) and carbon tetrachloride (Chen et al 2014), and are found in other organ toxicities including in the lung (Cho et al 2015) and nasal cavity (Dunnick et al 2015). …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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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 was 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 (BMDL) 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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…Nanostring Analysis: NanoString nCounter (NanoString, Seattle, WA, USA) was used as a multiplexed gene expression platform to test for specific transcripts as previously described [ 104 ]. Briefly, non-cross-reactive probes were custom synthesized and mixed to validate transcript expression after normalization with housekeeping transcripts ( Actb ; Gapdh , Hprt , Rpl32 ) that were determined by RNA-seq to be treatment stable.…”

Section: Methodsmentioning

confidence: 99%

Insights into Repeated Renal Injury Using RNA-Seq with Two New RPTEC Cell Lines

Merrick,

Martin,

Brooks

et al. 2023

IJMS

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Renal proximal tubule epithelial cells (RPTECs) are a primary site for kidney injury. We created two RPTEC lines from CD-1 mice immortalized with hTERT (human telomerase reverse transcriptase) or SV40 LgT antigen (Simian Virus 40 Large T antigen). Our hypothesis was that low-level, repeated exposure to subcytotoxic levels of 0.25–2.5 μM cisplatin (CisPt) or 12.5–100 μM aflatoxin B1 (AFB1) would activate distinctive genes and pathways in these two differently immortalized cell lines. RNA-seq showed only LgT cells responded to AFB1 with 1139 differentially expressed genes (DEGs) at 72 h. The data suggested that AFB1 had direct nephrotoxic properties on the LgT cells. However, both the cell lines responded to 2.5 μM CisPt from 3 to 96 h expressing 2000–5000 total DEGs. For CisPt, the findings indicated a coordinated transcriptional program of injury signals and repair from the expression of immune receptors with cytokine and chemokine secretion for leukocyte recruitment; robust expression of synaptic and substrate adhesion molecules (SAMs) facilitating the expression of neural and hormonal receptors, ion channels/transporters, and trophic factors; and the expression of nephrogenesis transcription factors. Pathway analysis supported the concept of a renal repair transcriptome. In summary, these cell lines provide in vitro models for the improved understanding of repeated renal injury and repair mechanisms. High-throughput screening against toxicant libraries should provide a wider perspective of their capabilities in nephrotoxicity.

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Introduction to Toxicologic Pathology

Parker

2019

Toxicologic Pathology for Non-Pathologists

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Molecular Changes in the Nasal Cavity after N, N-dimethyl-p-toluidine Exposure

Cited by 4 publications

References 68 publications

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

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

Insights into Repeated Renal Injury Using RNA-Seq with Two New RPTEC Cell Lines

Introduction to Toxicologic Pathology

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