Oxidative stress (OS) mechanisms are speculated to play a significant role in nickel-induced toxic effects and their carcinogenic potency. Although nickel-induced oxidative damage in somatic tissues is well demonstrated, evidence of the involvement of a similar mechanism(s) in nickel-induced testicular dysfunction and associated genotoxic effects is scarce. Hence, the present study aimed to investigate the nickel-induced OS response in testis and the associated genotoxic implications in vivo. Initially, the toxicity profile of nickel chloride was determined in adult albino mice (CFTSwiss) following administration (intraperitoneal) of single doses. Subsequently, multiple sublethal doses (1.25, 2.5, and 5.0 mol/100 g of body weight per day for 3 days) were used to characterize effects on testicular histoarchitecture, lipid peroxidation (LPO) in testis (homogenates, microsomal or mitochondrial fractions) and epididymal sperm, DNA damage, induction of apoptosis in testis, and incidence of sperm head abnormalities. Although short-term doses of nickel induced only a minimal LPO response, multiple doses elicited a moderate (15% to 30%) increase in LPO in whole homogenates and higher dose-related increases in both mitochondrial (20% to 50%) and microsomal fractions (25% to 60%). This was associated with a significant increase in DNA damage in the testis as evidenced by increased single-strand breaks (fluorimetric analysis of DNA unwinding assay). Further, at higher doses, nickel-induced apoptosis was demonstrable in the testis biochemically. Although caudal sperm counts determined at all sampling weeks showed no alterations, analysis for head abnormalities revealed a nearly 3-to 4-fold increase in the percentage of abnormal sperms among the nickel-treated males during the first 3 weeks. Furthermore, mating of nickel-treated (2.5 mol/100 g of body weight per day for 5 days) males sequentially for a period of 5 weeks with untreated females resulted in a significant increase in male-mediated dominant lethaltype mutations (the frequency of dead implantations) during the first 3 weeks, suggesting a stage-specific effect on postmeiotic germ cells. These findings suggest that testicular toxicity of nickel compounds may be related to enhanced production of reactive oxygen species, probably mediated through oxidative damage to macromolecules, including damage to DNA.

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Introduction: Atherosclerosis is the leading cause of cardiovascular diseases (CVDs). Over the past three decades, the clinical focus has been reducing plasma lipids and other traditional risk factors to reduce cardiovascular mortality. More recently, the CANTOS trial showed that inflammation is a significant additional risk factor for CVDs. Regulatory T cells (Tregs) are well known to protect the aorta from the inflammatory burden, but clinically how to induce these cells is not known. Hypothesis: LDLr is expressed on various immune cells, including Tregs. Recently, our lab found that modulating the lipid metabolism through LDLr in Tregs protects mice from colitis. Collectively, our data illustrate that LDLr plays an essential role in T cell homeostasis and function that may impact atherosclerosis progression. Therefore, our goal in this study is to test whether the absence of LDLr in immune cells alters the development of atherosclerosis. Methods: We used C57BL/6J male mice, which were lethally irradiated and transplanted with either LDLr-/- or WT bone marrow (BMT). To induce atherosclerosis, we blocked hepatic triglyceride clearance (antisense oligonucleotides) and fed mice with a high-fat diet for 12 weeks. We then collected blood and aorta to assess the extent of atherosclerosis. Results: Mice transplanted with LDLr-/- bone marrow have a lower percentage of T lymphocytes such as Th1 cells, Th1/Th2 hybrid cells, and pro-inflammatory M1 macrophages in the aorta compared to WT BMT aorta. Conversely, LDLr-/- BMT mice had a lower percentage of total Tregs but a significantly higher percentage of Tregs expressing the anti-inflammatory cytokine IL-10 and a lower percentage of Tregs co-expressing the pro-inflammatory marker T-bet compared to WT BMT aorta. Also, LDLr-/- BMT mice exhibited a 2-fold increase in plasma IL-10 compared to WT BMT plasma. Conclusion: Altogether, the current study's finding suggests that the loss of the LDLr in the immune compartment (bone marrow) can induce a significant change in the aortic immune cells and may be a future target for augmenting the protective Tregs population in CVD patients.