title: Effects of Combined Exposure to Lead and High-Fat Diet on Bone Quality in Juvenile Male Mice.
abstract: BACKGROUND
  Lead (Pb) exposure and obesity are co-occurring risk factors for decreased bone mass in the young, particularly in low socioeconomic communities.
  
  
  OBJECTIVE
  The goal of this study was to determine whether the comorbidities of Pb exposure and high-fat diet-induced obesity amplify skeletal deficits independently associated with each of these risk factors, and to explore associated mechanisms of the observed deficiencies.
  
  
  METHODS
  Five-week-old male C57BL/6J mice were placed on low-fat (10% kcal, LFD) or high-fat (60% kcal, HFD) diets for 12 weeks. Mice were exposed to lifetime Pb (50 ppm) through drinking water.
  
  
  RESULTS
  HFD was associated with increased body mass and glucose intolerance. Both HFD and Pb increased fasting glucose and serum leptin levels. Pb and HFD each reduced trabecular bone quality and together had a further detrimental effect on these bone parameters. Mechanical bone properties of strength were depressed in Pb-exposed bones, but HFD had no significant effect. Both Pb and HFD altered progenitor cell differentiation, promoting osteoclastogenesis and increasing adipogenesis while suppressing osteoblastogenesis. In support of this lineage shift being mediated through altered Wnt signaling, Pb and non-esterified fatty acids in MC3T3 cells increased in vitro PPAR-γ activity and inhibited β-catenin activity. Combining Pb and non-esterified fatty acids enhanced these effects.
  
  
  CONCLUSIONS
  Pb and HFD produced selective deficits in bone accrual that were associated with alterations in progenitor cell activity that may involve reduced Wnt signaling. This study emphasizes the need to assess toxicants together with other risk factors relevant to human health and disease.
authors: Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York, USA.
authors: Eric E
authors: EE
authors: Beier
authors: Jason A
authors: JA
authors: Inzana
authors: Tzong-Jen
authors: TJ
authors: Sheu
authors: Lei
authors: L
authors: Shu
authors: J Edward
authors: JE
authors: Puzas
authors: Robert A
authors: RA
authors: Mooney
mesh_terms: D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004785:Environmental Pollutants / Q000633:toxicity*; D007854:Lead / Q000633:toxicity*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000139:chemically induced; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D004785:Environmental Pollutants; D007854:Lead