The Xanthine Oxidoreductase Inhibitor Febuxostat Protects Against Nanomaterial Inhalation-Induced Microvascular and Reproductive Dysfunction During Gestation

Details

• Personal Author:
  Batchelor TP ; Bowdridge E ; DeVallance E ; Goldsmith WT ; Griffith J ; Hussain S ; Kelley E ; Nurkiewicz T ; Wix K
• Description:
  Maternal inhalation exposure to nano-TiO2 during gestation impacts litter size, pup and placental mass, 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), rescues the poor microvascular and reproductive outcomes induced by gestational nano-TiO2 exposure. Female Sprague Dawley rats, 6-8 weeks of age, received febuxostat treated water (50 mg/L) beginning 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 = 4) or nano-TiO2 (N = 4) 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 before sacrifice on GD 20. Dam and litter characteristics as well as placental and fetal weights were recorded at the time of sacrifice. No significant differences were observed between sham-control and nano-TiO2 groups for litter size (9.6 +/- 3.3 versus 12.6 +/- 2.2), fetal (3.8 +/- 0.1 g versus 4.0 +/- 0.9 g) or placental mass (0.72 +/- 0.03 g versus 0.65 +/- 0.02 g). 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), and decreased kisspeptin induced vasoconstriction from what has been previously observed in directly exposed nano-TiO2 dams (75.1% +/- 14.2). 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, liver, and microvascular functions are protected, at least in part, from nano-TiO2 inhalation exposure induced dysfunction in pregnant dams by XOR inhibition. [Description provided by NIOSH]
• Subjects:
  Animals Enzymes Occupational Health Pregnancy Respiratory System Safety Titanium
• Keywords:
  Animal Studies Inhalation Studies Nanoparticles Prenatal Exposure Titanium Dioxide
• ISSN:
  1096-6080
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Abstract or Summary
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  192
• NIOSHTIC Number:
  nn:20067213
• Citation:
  Toxicologist 2023 Mar; 192(S1):210
• CAS Registry Number:
  Titania (CAS RN 13463-67-7)
• Federal Fiscal Year:
  2023
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  West Virginia University
• Peer Reviewed:
  False
• Start Date:
  20220901
• Source Full Name:
  The Toxicologist. Society of Toxicology 62nd Annual Meeting & ToxExpo, March 19-23, 2023, Nashville, Tennessee
• End Date:
  20250831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:2290772fff057b62d08e2b0ceba4431b71599daeb297603f16108751bfeea3a19423b927ad89d26df274220dae05542b8b1452e7d53b8e76503999f30235f4a0
• Download URL:
  https://stacks.cdc.gov/view/cdc/231340/cdc_231340_DS1.pdf
• File Type:
  [PDF - 1.07 MB ]