ACUTE EXPOSURE TO NANO‐TIO2 PARTICLES CAUSES SEVERE ENDOTHELIUM‐ DEPENDENT DYSFUNCTION IN THE MIDDLE CEREBRAL ARTERY

Abstract

BackgroundThe use of engineered nanomaterials (ENM) is increasing; however, proper EMN toxicological assessments are typically incomplete. Previous studies demonstrate that ENM exposure is linked to adverse cardiovascular outcomes, including stroke. The cerebral microcirculation is key in regulating cerebral blood flow and any dysfunction may increase the risk of stroke. The direct impact of exposure to nano‐titanium dioxide (TiO2) on cerebral microvasculature is unknown.MethodsTo determine whether acute nano‐TiO2 exposure causes cerebral endothelial dysfunction, intratracheal instillation was used to deliver 240 μg of TiO2 suspended in 300 μl of sterile PBS vehicle to male and female Sprague‐Dawley rats 24 hours prior to surgery. The middle cerebral arteries (MCAs) were isolated and hung in a pressurized myobath. To assess endothelial‐dependent function, MCAs were challenged with increasing doses of acetylcholine (ACh; endo dependent dilation) and phenylephrine (PE; α‐adrenergic‐mediated constrictor). As endothelial dysfunction can be caused by oxidative stress, possibly through increased xanthine oxidase activity. To explore this, MCAs were incubated with Febuxostat (10 μM), a xanthine oxidase inhibitor, for 30 mins prior to treatment with Ach. To examine the effects of oxidative stress on MCA function we then exposed MCAs to the XO‐specific inhibitor, febuxostat (10 μM) for 30 min prior to ACh‐induced dilation.ResultsTiO2 exposure decreased MCA endothelium‐dependent dilation (p<0.05) in both sexes. However, febuxostat treatment restored the impaired dilation response in male rats, whereas no effect was observed in females. Interestingly, PE‐induced constriction of MCAs was also attenuated (p<0.05) in rats exposed to nano‐TiO2 compared to controls, suggesting overall MCA function was significantly decreased with nano‐TiO2 exposure.ConclusionThese data provide evidence that acute exposure to nano‐TiO2 significantly impairs MCA endothelium‐dependent dilation and constriction. However, incubation with a XO inhibitor limits this dysfunction but only in males, suggesting 1) a contributory role for XO in mediating TiO2 toxicity in the vasculature, and 2) an interesting sex‐related difference in the compromised cerebral microvascular health after nano‐TiO2 exposure. Experiments are underway to discover the underlying mechanism(s) that contribute to these observations.Support or Funding InformationNIH ES015022 (TRN); NIHGMS 1P20 GM‐109098 (PDC), AHA 16PRE30820000 (ED)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.