Sex differences in the acute and subchronic lung inflammatory responses of mice to nickel nanoparticles

• Published in: Nanotoxicology Vol. 14; no. 8; pp. 1058 - 1081
• Main Authors: You, Dorothy J., Lee, Ho Young, Taylor-Just, Alexia J., Linder, Keith E., Bonner, James C.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 13.09.2020; Taylor & Francis Ltd
• Subjects: Alveoli; Animals; Bronchoalveolar Lavage Fluid - cytology; Bronchus; Chemokine CXCL1 - metabolism; Cytokines; Exposure; Female; Females; Gender aspects; Gender differences; Humans; Inflammation; Inflammatory response; Inhalation Exposure; Interleukin 6; Interleukin-6 - metabolism; Leukocytes (neutrophilic); Lipopolysaccharides; Liver; lung; Lung - drug effects; Lung - immunology; Lung - pathology; Lung diseases; Male; Males; Metal Nanoparticles - toxicity; Mice; Mice, Inbred C57BL; Monocyte chemoattractant protein 1; Monocytes; Nanoparticles; Nanotechnology; Necropsy; Neutrophilia; Neutrophils - cytology; Neutrophils - drug effects; Nickel; Nickel - toxicity; Nickel nanoparticles; Phosphorylation; Pneumonia - chemically induced; Pneumonia - pathology; Rodents; Sex; Sex Characteristics; Sex differences; Signal Transduction; STAT Transcription Factors - metabolism; Stat1 protein; Stat3 protein; susceptibility; Tissues; Toxicity Tests, Acute; Toxicity Tests, Subchronic; Transcription factors; lung; susceptibility; inflammation; sex; Nickel nanoparticles
• ISSN: 1743-5390; 1743-5404
• DOI: 10.1080/17435390.2020.1808105

Nickel nanoparticles (NiNPs) are increasingly used in nanotechnology applications, yet information on sex differences in NiNP-induced lung disease is lacking. The goal of this study was to explore mechanisms of susceptibility between male and female mice after acute or subchronic pulmonary exposure to NiNPs. For acute exposure, male and female mice received a single dose of NiNPs with or without LPS by oropharyngeal aspiration and were necropsied 24 h later. For subchronic exposure, mice received NiNPs with or without LPS six times over 3 weeks prior to necropsy. After acute exposure to NiNPs and LPS, male mice had elevated cytokines (CXCL1 and IL-6) and more neutrophils in bronchoalveolar lavage fluid (BALF), along with greater STAT3 phosphorylation in lung tissue. After subchronic exposure to NiNPs and LPS, male mice exhibited increased monocytes in BALF. Moreover, subchronic exposure of male mice to NiNP only induced higher CXCL1 and CCL2 in BALF along with increased alveolar infiltrates and CCL2 in lung tissue. STAT1 in lung tissue was induced by subchronic exposure to NiNPs in females but not males. Males had a greater induction of IL-6 mRNA in liver after acute exposure to NiNPs and LPS, and greater CCL2 mRNA in liver after subchronic NiNP exposure. These data indicate that susceptibility of males to acute lung inflammation involves enhanced neutrophilia with increased CXCL1 and IL-6/STAT3 signaling, whereas susceptibility to subchronic lung inflammation involves enhanced monocytic infiltration with increased CXCL1 and CCL2. STAT transcription factors appear to play a role in these sex differences. This study demonstrates sex differences in the lung inflammatory response of mice to NiNPs that has implications for human disease.