The aim of this study was to determine whether repeated exposure to iron oxide nanoparticles (Fe O -NPs) could be toxic to mice testis. Fe O -NPs (25 and 50 mg/kg) were intraperitoneally administered into mice once a week for 4 weeks. Our study showed that Fe O -NPs have the ability to cross the blood-testis barrier to get into the testis. The findings showed that exposure resulted in the accumulation of Fe O -NPs which was evidenced from the iron content and accumulation in the testis. Furthermore, 25 and 50 mg/kg Fe O -NPs administration increased the reactive oxygen species, lipid peroxidation, protein carbonyl content, glutathione peroxidase activity, and nitric oxide levels with a concomitant decrease in the levels of antioxidants-superoxide dismutase, catalase, glutathione, and vitamin C. Increased expression of Bax, cleaved-caspase-3, and cleaved-PARP confirms apoptosis. Serum testosterone levels increased with increased concentration of Fe O -NPs exposure. In addition, the histopathological lesions like vacuolization, detachment, and sloughing of germ cells were also observed in response to Fe O -NPs treatment. The data from our study entailed that testicular toxicity caused by Fe O -NPs exposure may be associated with Fe O -NPs accumulation leading to oxidative stress and apoptosis. Therefore, precautions should be taken in the safe use of Fe O -NPs to avoid complications in the fertility of males. Further research will unravel the possible molecular mechanisms on testicular toxicity of Fe O -NPs. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 594-608, 2017.

Iron oxide nanoparticles (FeO-NPs) are widely used in various biomedical applications, extremely in neurotheranostics. Simultaneously, FeO-NP usage is of alarming concern, as its exposure to living systems causes deleterious effects due to its redox potential. However, study on the neurobehavioural impacts of FeO-NPs is very limited. In this regard, adult male mice were intraperitoneally administered with FeO-NPs (25 and 50 mg/kg body weight) once a week for 4 weeks. A significant change in locomotor behaviour and spatial memory was observed in FeO-NP-treated animals. Damages to blood-brain barrier permeability by FeO-NPs and their accumulation in brain regions were evidenced by Evan's blue staining, iron estimation and Prussian blue staining. Elevated nitric oxide, acetylcholinesterase, lactate dehydrogenase leakage and demyelination were observed in the FeO-NP-exposed brain tissues. Imbalanced levels of ROS generation and antioxidant defence mechanism (superoxide dismutase and catalase) cause damages to lipids, proteins and DNA. PARP and cleaved caspase 3 expression levels were found to be increased in the FeO-NP-exposed brain regions which confirms DNA damage and apoptosis. Thus, repeated FeO-NP exposure causes neurobehavioural impairments by nanoparticle accumulation, oxidative stress and apoptosis in the mouse brain.

Objective: Hypercholesterolemia-induced NETosis and accumulation of neutrophil extracellular traps (NETs) in the atherosclerotic lesion exacerbates inflammation and is causally implicated in plaque progression. We investigated whether hypercholesterolemia additionally impairs the clearance of NETs mediated by endonucleases such as DNase1 and DNase1L3 and its implication in advanced atherosclerotic plaque progression. Approach and Results: Using a mouse model, we demonstrate that an experimental increase in the systemic level of NETs leads to a rapid increase in serum DNase activity, which is critical for the prompt clearance of NETs and achieving inflammation resolution. Importantly, hypercholesterolemic mice demonstrate an impairment in this critical NET-induced DNase response with consequent delay in the clearance of NETs and defective inflammation resolution. Administration of TUDCA, a chemical chaperone that relieves endoplasmic reticulum stress, rescued the hypercholesterolemia-induced impairment in the NET-induced DNase response suggesting a causal role for endoplasmic reticulum stress in this phenomenon. Correction of the defective DNase response with exogenous supplementation of DNase1 in Apoe −/− mice with advanced atherosclerosis resulted in a decrease in plaque NET content and significant plaque remodeling with decreased area of plaque necrosis and increased collagen content. From a translational standpoint, we demonstrate that humans with hypercholesterolemia have elevated systemic extracellular DNA levels and decreased plasma DNase activity. Conclusions: These data suggest that hypercholesterolemia impairs the NET-induced DNase response resulting in defective clearance and accumulation of NETs in the atherosclerotic plaque. Therefore, strategies aimed at rescuing this defect could be of potential therapeutic benefit in promoting inflammation resolution and atherosclerotic plaque stabilization.

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