Titanium Dioxide Nanoparticle Exposure Provokes Greater Lung Inflammation in Females Than Males in the Context of Obesity

Ji-Soo Jeong,1,* Hyun Jegal,2,* Je-Won Ko,1,* Jeong-Won Kim,1,3 Jin-Hwa Kim,1 Eun-Hye Chung,1 So-Young Boo,1 Su-Ha Lee,1 Ga-Won Lee,2,4 Se-Myo Park,2 Mi-Sun Choi,2 Hyoung-Yun Han,2,4 Tae-Won Kim1 1College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, Daejeon, 34131, Republic of Korea; 2Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea; 3Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Science, Seoul, 01812, Republic of Korea; 4Department of Human and Environmental Toxicology, University of Science & Technology, Daejeon, 34113, Republic of Korea*These authors contributed equally to this workCorrespondence: Hyoung-Yun Han, Email [email protected] Tae-Won Kim, Email [email protected]: Obesity is a chronic metabolic disease responsible for causing various health problems. Obese individuals experience disrupted homeostasis, thus making them more vulnerable to environmental pollutants. This study investigated the effect of pre-existing obesity on respiratory toxicity and explored whether sex differences exist in the response to titanium dioxide nanoparticles (TiO2-NPs), a component of air pollutants.Methods: Male and female mice were fed a normal diet (ND) or a high-fat diet (HFD) for 26 weeks and then intratracheally instilled with TiO2-NPs at concentrations of 0, 0.1, 0.2, and 0.4 mg/50 μL on days 1, 4, 6, 9, 11, and 13. Mice were sacrificed 24 h after the final administration.Results: In HFD-fed obese mice, TiO2-NPs exposure led to respiratory inflammation through the toll-like receptor 4-mediated mitogen-activated protein kinase signaling pathway and a subsequent inflammatory response induced by oxidative stress. These effects were more pronounced in females than in males, and this was attributed to the higher sensitivity of females to HFD consumption and early depletion of antioxidant defenses.Conclusion: Our findings suggest an increased risk of respiratory toxicity in individuals with pre-existing obesity and highlight that these effects are sex-specific. Keywords: nanoparticles, high-fat diet, respiratory toxicity, oxidative stress, inflammatory response