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

Abstract

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.

Keywords:

• Nickel nanoparticles
• inflammation
• lung
• sex
• susceptibility

Ethical approval

Ethics approval for animal use was given by the North Carolina State University IACUC.

Author contributions

DJY and JCB conceived and planned the experiments. DJY, HYL, AJT, and JCB carried out experiments and quantitative analysis. DJY, HYL, AJT, KEL, and JCB contributed to the interpretation of the results. KEL provided pathology support and unbiased scoring of lung inflammatory lesions. DJY took the lead in writing the manuscript. All authors provided critical feedback and helped shape the research, analysis, and manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Additional information

Funding

This work was supported by National Institute of Environmental Health [R01ES020897] (DJY, HYL, AJT, JCB), National Institute of Environmental Health Training Grant [T32 ES007046] (DJY, HYL), and National Institute of Environmental Health [P30 ES025128] (KEL, JCB).