Pulmonary Toxicity of Nickel Oxide Nanoparticles in a Transgenic Mouse Model Expressing Humanized Toll-Like Receptor-4 (TLR-4)

Details

• Personal Author:
  Aldinger JL ; Roach KA ; Roberts, Jennifer R. ; Stefaniak, Aleksandr B.
• Description:
  Background and Purpose: We have previously demonstrated that murine expression of humanized Toll-like receptor-4 (hTLR-4) confers enhanced immunological responsivity to nickel in the skin and increased susceptibility to contact sensitization in vivo; however, it remains unclear if hTLR-4 expression is similarly implicated in inflammatory reactions elicited by nickel in other relevant tissues. Consequently, the primary goal of this study was to characterize the effects of nickel nanoparticles on the lung in both sexes and genotypes of mice from the hTLR-4 colony to help elucidate its potential utility for future studies of nickel's health effects. Methods: hTLR-4 negative and positive mice of both sexes (n=6 per group) were exposed to vehicle control (dispersion media, DM) or nickel oxide nanoparticles (NiONP, 48 nm) in one of three doses (2.5, 5, or 20 µg) once by oropharyngeal aspiration (0 d). Mice were euthanized 1, 7, 14, or 28 d post-exposure and bronchoalveolar lavage (BAL) was performed to evaluate cellular constituents and biochemical indices of inflammation. Results: The highest dose of NiONP induced significant increases in BAL lactate dehydrogenase (LDH) activity in all groups, the magnitude of which, was dependent on sex and genotype. Overall, females were more sensitive to LDH responses than males, while hTLR-4 expression was associated with greater maximal LDH values in both sexes (374 vs 239 U/L in females, 251 vs 189 U/L in males). A similar trend was observed with respect to total BAL cell number, which increased to the greatest degree in female hTLR-4 positive mice at 7 d (4.1x increase over DM). BAL cell count increased 2.3- fold over DM control values in hTLR-4 negative females, 2.1x in hTLR-4 negative males, and 2.6x in hTLR-4 positive males. BAL neutrophil number also peaked in NiONP-exposed females at 7 d, constituting 36.5% of the total BAL cell pool in hTLR-4 negative animals and 59.9% in the hTLR-4 positive group. Neutrophil counts peaked between 7 and 14 d in males and comprised 38.5% (hTLR-4 negative) and 37.8% (hTLR-4 positive) of all BAL cells. BAL macrophage activation status was differentially impacted by hTLR-4 genotype in female and male mice. Interestingly, the greatest increase in macrophage activation was seen in hTLR-4 negative females at 14 d (36.5%), despite a lack of significance at 1 d (4.9%) and 7 d (5.2%). In hTLR-4 positive females, activation status was significantly increased at all time points of the study but peaked on 7 d at 32.4%. Unlike in females, the time course of macrophage activation in male mice was consistent between groups, reaching peak values at 14 d (17.7% in hTLR-4 negative males, 22.3% in hTLR-4 positive). Conclusions: Overall, hTLR-4 positive mice exhibited a significantly greater degree of biological responsivity to NiONP than same-sex hTLR-4 negative controls. Female mice were generally more susceptible to nickel-induced airway inflammation than males, and the greatest maximal responses for most markers of interest in the study were observed in hTLR-4 positive females. These findings are consistent with information obtained previously from our hTLR-4 skin studies, collectively suggesting that the hTLR-4 mouse strain is able to more accurately emulate acute inflammatory responses to nickel in humans. [Description provided by NIOSH]
• Subjects:
  Immune System Laboratories Lung Occupational Health Respiratory System Safety Toxicology
• Keywords:
  Genotype Immune Reaction Laboratory Animals Nanoparticles Nickel Oxide Pulmonary Effects
• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division ; RHD - Respiratory Health Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  315-316
• Volume:
  198
• NIOSHTIC Number:
  nn:20069341
• Citation:
  Toxicologist 2024 Mar; 198(S1):315-316
• CAS Registry Number:
  Nickel monoxide (CAS RN 1313-99-1)
• Federal Fiscal Year:
  2024
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 63rd Annual Meeting & ToxExpo, March 10-14, 2024, Salt Lake City, Utah
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:6761786d608f8e307a7cf2ad5347c6cbea4f93c7d575b6d43a7b4e16030a93029eb9df469c9e4d0789e539dfa182f3ca83da57da02405f07b6175274e1d08a5b
• Download URL:
  https://stacks.cdc.gov/view/cdc/207839/cdc_207839_DS1.pdf
• File Type:
  [PDF - 540.38 KB ]