SAT641 The Xanthine Oxidoreductase Inhibitor, Febuxostat, Protects Against Nanomaterial Inhalation-induced Endocrine, Microvascular And Reproductive Dysfunction During Gestation

Abstract

Abstract Disclosure: E. Bowdridge: None. A. Dunn: None. J. Griffith: None. E. DeVallance: None. E. Kelley: None. S. Lewis: None. Maternal inhalation exposure to nano-TiO2 during gestation impacts litter size, pup and placental mass, circulating estrogen concentration, and uterine microvascular reactivity. In addition, we have recently shown that maternal inhalation of nano-TiO2 during gestation results in redox imbalance in dams during late gestation. However, the mechanism linking these dysfunctions with exposure has yet to be explored. Therefore, we hypothesized that elevated xanthine oxidoreductase (XOR), a critical source of oxidants in numerous inflammatory processes, is at least partially responsible for the increased oxidant production observed. The objective of this study was to assess if treatment with a XOR inhibitor, febuxostat (Uloric®), prevents the poor microvascular, reproductive, and endocrine outcomes induced by gestational nano-TiO2 exposure. Female Sprague Dawley rats, 6-8 weeks of age, received febuxostat treated water (50 mg/L) one week prior to being mated in-house and throughout gestation until sacrifice on gestational day (GD) 20. Once pregnant, dams were randomly assigned to either sham-control (N = 6) or nano-TiO2 (N = 6) groups. Dams were exposed (nano-TiO2 concentration = 12 mg/m3; HEPA-filtered air 25 ml/min) for 6 hrs/d for 6 d between GD 10-19. Dam and litter characteristics as well as placental and fetal weights were recorded on GD 20. Dam blood samples were obtained at the time of sacrifice to determine xanthine oxidase and estrogen concentrations. No significant differences were observed between sham-control and nano-TiO2 groups for litter size (8.8±2.1 versus 9.8±2.1), or fetal mass (3.9±0.1 g versus 4.0±0.1 g). However, placental mass (0.72±0.03 g versus 0.62±0.02 g) was significantly reduced in the nano-TiO2 group. There was no significant difference in circulating estrogen between control rats given febuxostat water (29.8±2.70 pg) and nano-TiO2 rats given febuxostat water (36.7±1.29 pg). However, nano-TiO2 rats treated with febuxostat water saw a significant increase in estrogen levels (36.7±1.29 pg) compared to nano-TiO2 rats without the febuxostat water (19.9±2.39 pg). Additionally, uterine arteries were isolated, and reactivity was assessed ex vivo. Uterine arteries from exposed females treated with febuxostat showed similar vasoconstriction to kisspeptin (97.6%±1.95) as control females given febuxostat (99.8%±0.61). Additionally, there was no difference in dam liver mass (11.5% ± 0.80 g control versus 13.9% ± 0.60 g nano-TiO2), which we have previously shown to be increased due to nano-TiO2 exposure. Taken together, these observations indicate that reproductive, endocrine, liver, and microvascular functions are protected, at least in part, from nano-TiO2 inhalation exposure induced dysfunction in pregnant dams by XOR inhibition. Presentation: Saturday, June 17, 2023