Sex differences in the acute nasal antioxidant/antielectrophilic response of the rat to inhaled naphthalene

Joseph A. Cichocki, Gregory J. Smith, Ryan Mendoza, Alan R Buckpitt, Laura S. Van winkle, John B. Morris

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Naphthalene is a nasal carcinogen, inducing respiratory adenomas in male and olfactory neuroblastomas in female rats, respectively. The reasons for the site and sex-specific tumorigenic response are unknown. Naphthalene is bioactivated to electrophilic metabolites; cytotoxicity followed by regenerative cell proliferation is likely involved in the tumorigenic response. To examine sex differences in the acute nasal response to naphthalene, male and female F344 rats were nose-only exposed to 0, 1, 3, 10, or 30 ppm naphthalene vapor for 4 or 6 h. Following exposure, respiratory/transitional mucosa (RTM) and olfactory mucosa (OM) were isolated and analyzed for markers of oxidant/electrophilic stress and/or toxicity, including reduced/oxidized glutathione levels (GSH/GSSG), mRNA levels of electrophile-responsive genes, and epithelial cytoxicity (as measured by membrane permeability to ethidium homodimer-1). Naphthalene caused significant depletion of GSH in RTM and OM with no increase in GSSG. Cytotoxicity was apparent at concentrations of 15 and 30 ppm. No consistent sex differences were observed in these responses. Sex differences were observed in the induction of antielectrophilic genes in OM: glutamyl cysteine ligase (catalytic subunit) (Gclc), NADPH quinone oxidase 1 (Nqo1), and heme oxygenase 1 (Hmox1) were all induced to a greater extent in the male OM compared with the female. No consistent sex differences were observed in the RTM. Although the mechanism of the sex difference in the RTM adenoma response remains enigmatic, sex differences in the induction of antioxidant/electrophile-responsive genes may contribute to the heightened sensitivity of the female OM to the carcinogenic effects of naphthalene.

Original languageEnglish (US)
Article numberkfu031
Pages (from-to)234-244
Number of pages11
JournalToxicological Sciences
Volume139
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Olfactory Mucosa
Nose
Sex Characteristics
Rats
Respiratory Mucosa
Antioxidants
Glutathione Disulfide
Adenoma
Genes
Olfactory Esthesioneuroblastoma
Cytotoxicity
Heme Oxygenase-1
Inbred F344 Rats
Ligases
Oxidants
Carcinogens
Glutathione
Cysteine
naphthalene
Mucous Membrane

Keywords

  • Antioxidants
  • Inhalation toxicology
  • Naphthalene
  • Nasal toxicity
  • Oxidative stress

ASJC Scopus subject areas

  • Toxicology
  • Medicine(all)

Cite this

Sex differences in the acute nasal antioxidant/antielectrophilic response of the rat to inhaled naphthalene. / Cichocki, Joseph A.; Smith, Gregory J.; Mendoza, Ryan; Buckpitt, Alan R; Van winkle, Laura S.; Morris, John B.

In: Toxicological Sciences, Vol. 139, No. 1, kfu031, 2014, p. 234-244.

Research output: Contribution to journalArticle

Cichocki, Joseph A. ; Smith, Gregory J. ; Mendoza, Ryan ; Buckpitt, Alan R ; Van winkle, Laura S. ; Morris, John B. / Sex differences in the acute nasal antioxidant/antielectrophilic response of the rat to inhaled naphthalene. In: Toxicological Sciences. 2014 ; Vol. 139, No. 1. pp. 234-244.
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