Preparation of Specific Compartments of the Lungs for Pathologic and Biochemical Analysis of Toxicologic Responses

Winkle, Laura S. Van; Kelty, Jacklyn Skye; Plopper, Charles G.

doi:10.1002/cptx.18

Cited by 8 publications

(3 citation statements)

References 52 publications

(93 reference statements)

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“…Mice were exposed to HEPA-filtered air (FA) or NA vapor (5 or 10 ppm) as described above, and sacrificed 20 hours after termination of the exposure, by CO 2 overdose. The lungs were inflated with Karnovsky’s solution as described previously (Van Winkle et al , 2001; Van Winkle et al , 2004; Van Winkle et al , 2017). Fixed lung lobes were embedded in Araldite 502 resin.…”

Section: Methodsmentioning

confidence: 99%

Impact of hepatic P450-mediated biotransformation on the disposition and respiratory tract toxicity of inhaled naphthalene

Kovalchuk

Kelty

et al. 2017

Toxicology and Applied Pharmacology

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We determined whether a decrease in hepatic microsomal cytochrome P450 activity would impact lung toxicity induced by inhalation exposure to naphthalene (NA), a ubiquitous environmental pollutant. The liver-Cpr-null (LCN) mouse showed decreases in microsomal metabolism of NA in liver, but not lung, compared to wild-type (WT) mouse. Plasma levels of NA and NA-glutathione conjugates (NA-GSH) were both higher in LCN than in WT mice after a 4-h nose-only NA inhalation exposure at 10ppm. Levels of NA were also higher in lung and liver of LCN, compared to WT, mice, following exposure to NA at 5 or 10ppm. Despite the large increase in circulating and lung tissue NA levels, the level of NA-GSH, a biomarker of NA bioactivation, was either not different, or only slightly higher, in lung and liver tissues of LCN mice, relative to that in WT mice. Furthermore, the extent of NA-induced acute airway injury, judging from high-resolution lung histopathology and morphometry at 20h following NA exposure, was not higher, but lower, in LCN than in WT mice. These results, while confirming the ability of extrahepatic organ to bioactivate inhaled NA and mediate NA's lung toxicity, suggest that liver P450-generated NA metabolites also have a significant, although relatively small, contribution to airway toxicity of inhaled NA. This hepatic contribution to the airway toxicity of inhaled NA may be an important risk factor for individuals with diminished bioactivation activity in the lung.

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Section: Methodsmentioning

confidence: 99%

Impact of hepatic P450-mediated biotransformation on the disposition and respiratory tract toxicity of inhaled naphthalene

Kovalchuk

Kelty

et al. 2017

Toxicology and Applied Pharmacology

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“…The mechanism of cancer initiation is unclear, however, so investigations of protein adducts, DNA adducts, and repair tolerance [66,67] have been conducted using NA and its metabolite, 1,2 naphthoquinone (NQ). Using well established techniques to obtain metabolically active, live tissue samples [68], freshly micro-dissected respiratory tissues were incubated with NA or NQ at 250 μM, calculated as equivalent to the tissue concentration obtained from exposure to the 10 ppm OSHA exposure limit for NA [69]. DNA adducts of NA and NQ are present in low levels, but protein adducts are much more common [66,67].…”

Section: Applicationsmentioning

confidence: 99%

Radiocarbon Tracers in Toxicology and Medicine: Recent Advances in Technology and Science

Malfatti

Buchholz

Enright

et al. 2019

Toxics

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This review summarizes recent developments in radiocarbon tracer technology and applications. Technologies covered include accelerator mass spectrometry (AMS), including conversion of samples to graphite, and rapid combustion to carbon dioxide to enable direct liquid sample analysis, coupling to HPLC for real-time AMS analysis, and combined molecular mass spectrometry and AMS for analyte identification and quantitation. Laser-based alternatives, such as cavity ring down spectrometry, are emerging to enable lower cost, higher throughput measurements of biological samples. Applications covered include radiocarbon dating, use of environmental atomic bomb pulse radiocarbon content for cell and protein age determination and turnover studies, and carbon source identification. Low dose toxicology applications reviewed include studies of naphthalene-DNA adduct formation, benzo[a]pyrene pharmacokinetics in humans, and triclocarban exposure and risk assessment. Cancer-related studies covered include the use of radiocarbon-labeled cells for better defining mechanisms of metastasis and the use of drug-DNA adducts as predictive biomarkers of response to chemotherapy.

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“…For additional studies of AChE in airway-specific tissues, trachealis muscle and airway tissue were also harvested. For airway tissue, right lung lobes were inflated with agarose, and isolated bronchiolar airway was harvested from this preparation by microdissecting away the lung parenchyma as described previously (Van Winkle et al, 2017). AChE-specific activity was assessed in these tissues using Ellman's assay as described previously (Ellman et al, 1961) using acetylthiocholine iodide as the substrate and tetraisopropylpyrophosphoramide (Sigma-Aldrich) to inhibit butyrylcholinesterase.…”

Section: Analysis Of Airway Resistance (R) and Tissue Elastance (E)mentioning

confidence: 99%

The Organophosphorus Pesticide Chlorpyrifos Induces Sex-Specific Airway Hyperreactivity in Adult Rats

Shaffo¹,

Grodzki²,

Schelegle

et al. 2018

Toxicological Sciences

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Occupational and environmental exposures to organophosphorus pesticides (OPs) are associated with increased incidence of asthma and other pulmonary diseases. Although the canonical mechanism of OP neurotoxicity is inhibition of acetylcholinesterase (AChE), it was previously reported that the OP chlorpyrifos (CPF) causes airway hyperreactivity (AHR) in guinea pigs at levels that do not inhibit lung or brain AChE. The guinea pig is considered to have inherently hyperresponsive airways, thus, cross-species validation is needed to confirm relevance to humans. Additionally, sex differences in asthma incidence have been demonstrated in the human population, but whether OP-induced AHR is sex-dependent has not been systematically studied in a preclinical model. In this study, 8-week old male and female Sprague Dawley rats were administered CPF at doses causing comparable AChE inhibition in whole lung homogenate (30 mg/kg in males, 7 mg/kg in females, sc) prior to assessing pulmonary mechanics in response to electrical stimulation of the vagus nerves at 24 h, 48 h, 72 h, 7 d or 14 d post-exposure in males, and 24 h or 7 d post-exposure in females. CPF significantly potentiated vagally induced airway resistance and tissue elastance at 7 d post-exposure in males, and at 24 h and 7 d post-exposure in females. These effects occurred independent of significant AChE inhibition in cerebellum, blood, trachealis, or isolated airway, suggesting that AChE independent OP-induced airway hyperreactivity is a cross-species phenomenon. These findings have significant implications for assessing the risk posed by CPF, and potentially other OPs, to human health and safety.

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Preparation of Specific Compartments of the Lungs for Pathologic and Biochemical Analysis of Toxicologic Responses

Cited by 8 publications

References 52 publications

Impact of hepatic P450-mediated biotransformation on the disposition and respiratory tract toxicity of inhaled naphthalene

Impact of hepatic P450-mediated biotransformation on the disposition and respiratory tract toxicity of inhaled naphthalene

Radiocarbon Tracers in Toxicology and Medicine: Recent Advances in Technology and Science

The Organophosphorus Pesticide Chlorpyrifos Induces Sex-Specific Airway Hyperreactivity in Adult Rats

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