Naphthalene cytotoxicity in microsomal epoxide hydrolase deficient mice

S. A. Carratt, D. Morin, Alan R Buckpitt, P. C. Edwards, L. S. Van Winkle

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Naphthalene (NA) is a ubiquitous pollutant to which humans are widely exposed. 1,2-Dihydro-1,2-dihydroxynaphthalene (NA-dihydrodiol) is a major metabolite of NA generated by microsomal epoxide hydrolase (mEH). To investigate the role of the NA-dihydrodiol and subsequent metabolites (i.e. 1,2-naphthoquinone) in cytotoxicity, we exposed both male and female wild type (WT) and mEH null mice (KO) to NA by inhalation (5, 10, 20 ppm for 4 h). NA-dihydrodiol was ablated in the KO mice. High-resolution histopathology was used to study site-specific cytotoxicity, and formation of naphthalene metabolites was measured by HPLC in microdissected airways. Swollen and vacuolated airway epithelial cells were observed in the intra- and extrapulmonary airways of all mice at and below the current OSHA standard (10 ppm). Female mice may be more susceptible to this acute cytotoxicity. In the extrapulmonary airways, WT mice were more susceptible to damage than KO mice, indicating that the metabolites associated with mEH-mediated metabolism could be partially responsible for cytotoxicity at this site. The level of cytotoxicity in the mEH KO mice at all airway levels suggests that non-mEH metabolites are contributing to NA cellular damage in the lung. Our results indicate that the apparent contribution of mEH-dependent metabolites to toxicity differs by location in the lung. These studies suggest that metabolites generated through the mEH pathway may be of minor importance in distal airway toxicity and subsequent carcinogenesis from NA exposure.

Original languageEnglish (US)
Pages (from-to)35-41
Number of pages7
JournalToxicology Letters
Volume246
DOIs
StatePublished - Mar 30 2016

Fingerprint

mouse EPHX1 protein
Epoxide Hydrolases
Cytotoxicity
Metabolites
Toxicity
United States Occupational Safety and Health Administration
naphthalene
Lung
Metabolism
Inhalation

Keywords

  • Carcinogen metabolism
  • Cell injury/cell death
  • Cytochrome P450
  • HPLC
  • Lung/pulmonary/olfactory
  • Microsomal epoxide hydrolase
  • Toxicology

ASJC Scopus subject areas

  • Toxicology

Cite this

Naphthalene cytotoxicity in microsomal epoxide hydrolase deficient mice. / Carratt, S. A.; Morin, D.; Buckpitt, Alan R; Edwards, P. C.; Van Winkle, L. S.

In: Toxicology Letters, Vol. 246, 30.03.2016, p. 35-41.

Research output: Contribution to journalArticle

Carratt, S. A. ; Morin, D. ; Buckpitt, Alan R ; Edwards, P. C. ; Van Winkle, L. S. / Naphthalene cytotoxicity in microsomal epoxide hydrolase deficient mice. In: Toxicology Letters. 2016 ; Vol. 246. pp. 35-41.
@article{0343310919f54720a3955f6d779eba89,
title = "Naphthalene cytotoxicity in microsomal epoxide hydrolase deficient mice",
abstract = "Naphthalene (NA) is a ubiquitous pollutant to which humans are widely exposed. 1,2-Dihydro-1,2-dihydroxynaphthalene (NA-dihydrodiol) is a major metabolite of NA generated by microsomal epoxide hydrolase (mEH). To investigate the role of the NA-dihydrodiol and subsequent metabolites (i.e. 1,2-naphthoquinone) in cytotoxicity, we exposed both male and female wild type (WT) and mEH null mice (KO) to NA by inhalation (5, 10, 20 ppm for 4 h). NA-dihydrodiol was ablated in the KO mice. High-resolution histopathology was used to study site-specific cytotoxicity, and formation of naphthalene metabolites was measured by HPLC in microdissected airways. Swollen and vacuolated airway epithelial cells were observed in the intra- and extrapulmonary airways of all mice at and below the current OSHA standard (10 ppm). Female mice may be more susceptible to this acute cytotoxicity. In the extrapulmonary airways, WT mice were more susceptible to damage than KO mice, indicating that the metabolites associated with mEH-mediated metabolism could be partially responsible for cytotoxicity at this site. The level of cytotoxicity in the mEH KO mice at all airway levels suggests that non-mEH metabolites are contributing to NA cellular damage in the lung. Our results indicate that the apparent contribution of mEH-dependent metabolites to toxicity differs by location in the lung. These studies suggest that metabolites generated through the mEH pathway may be of minor importance in distal airway toxicity and subsequent carcinogenesis from NA exposure.",
keywords = "Carcinogen metabolism, Cell injury/cell death, Cytochrome P450, HPLC, Lung/pulmonary/olfactory, Microsomal epoxide hydrolase, Toxicology",
author = "Carratt, {S. A.} and D. Morin and Buckpitt, {Alan R} and Edwards, {P. C.} and {Van Winkle}, {L. S.}",
year = "2016",
month = "3",
day = "30",
doi = "10.1016/j.toxlet.2016.01.019",
language = "English (US)",
volume = "246",
pages = "35--41",
journal = "Toxicology Letters",
issn = "0378-4274",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - Naphthalene cytotoxicity in microsomal epoxide hydrolase deficient mice

AU - Carratt, S. A.

AU - Morin, D.

AU - Buckpitt, Alan R

AU - Edwards, P. C.

AU - Van Winkle, L. S.

PY - 2016/3/30

Y1 - 2016/3/30

N2 - Naphthalene (NA) is a ubiquitous pollutant to which humans are widely exposed. 1,2-Dihydro-1,2-dihydroxynaphthalene (NA-dihydrodiol) is a major metabolite of NA generated by microsomal epoxide hydrolase (mEH). To investigate the role of the NA-dihydrodiol and subsequent metabolites (i.e. 1,2-naphthoquinone) in cytotoxicity, we exposed both male and female wild type (WT) and mEH null mice (KO) to NA by inhalation (5, 10, 20 ppm for 4 h). NA-dihydrodiol was ablated in the KO mice. High-resolution histopathology was used to study site-specific cytotoxicity, and formation of naphthalene metabolites was measured by HPLC in microdissected airways. Swollen and vacuolated airway epithelial cells were observed in the intra- and extrapulmonary airways of all mice at and below the current OSHA standard (10 ppm). Female mice may be more susceptible to this acute cytotoxicity. In the extrapulmonary airways, WT mice were more susceptible to damage than KO mice, indicating that the metabolites associated with mEH-mediated metabolism could be partially responsible for cytotoxicity at this site. The level of cytotoxicity in the mEH KO mice at all airway levels suggests that non-mEH metabolites are contributing to NA cellular damage in the lung. Our results indicate that the apparent contribution of mEH-dependent metabolites to toxicity differs by location in the lung. These studies suggest that metabolites generated through the mEH pathway may be of minor importance in distal airway toxicity and subsequent carcinogenesis from NA exposure.

AB - Naphthalene (NA) is a ubiquitous pollutant to which humans are widely exposed. 1,2-Dihydro-1,2-dihydroxynaphthalene (NA-dihydrodiol) is a major metabolite of NA generated by microsomal epoxide hydrolase (mEH). To investigate the role of the NA-dihydrodiol and subsequent metabolites (i.e. 1,2-naphthoquinone) in cytotoxicity, we exposed both male and female wild type (WT) and mEH null mice (KO) to NA by inhalation (5, 10, 20 ppm for 4 h). NA-dihydrodiol was ablated in the KO mice. High-resolution histopathology was used to study site-specific cytotoxicity, and formation of naphthalene metabolites was measured by HPLC in microdissected airways. Swollen and vacuolated airway epithelial cells were observed in the intra- and extrapulmonary airways of all mice at and below the current OSHA standard (10 ppm). Female mice may be more susceptible to this acute cytotoxicity. In the extrapulmonary airways, WT mice were more susceptible to damage than KO mice, indicating that the metabolites associated with mEH-mediated metabolism could be partially responsible for cytotoxicity at this site. The level of cytotoxicity in the mEH KO mice at all airway levels suggests that non-mEH metabolites are contributing to NA cellular damage in the lung. Our results indicate that the apparent contribution of mEH-dependent metabolites to toxicity differs by location in the lung. These studies suggest that metabolites generated through the mEH pathway may be of minor importance in distal airway toxicity and subsequent carcinogenesis from NA exposure.

KW - Carcinogen metabolism

KW - Cell injury/cell death

KW - Cytochrome P450

KW - HPLC

KW - Lung/pulmonary/olfactory

KW - Microsomal epoxide hydrolase

KW - Toxicology

UR - http://www.scopus.com/inward/record.url?scp=84957810395&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84957810395&partnerID=8YFLogxK

U2 - 10.1016/j.toxlet.2016.01.019

DO - 10.1016/j.toxlet.2016.01.019

M3 - Article

C2 - 26840748

AN - SCOPUS:84957810395

VL - 246

SP - 35

EP - 41

JO - Toxicology Letters

JF - Toxicology Letters

SN - 0378-4274

ER -