Background: Lead (Pb) exposure and obesity are co-occurring risk factors for decreased bone mass in the young, particularly in low socioeconomic communities.

Objectives: 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.

Citation: Beier EE, Inzana JA, Sheu TJ, Shu L, Puzas JE, Mooney RA. 2015. Effects of combined exposure to lead and high-fat diet on bone quality in juvenile male mice. Environ Health Perspect 123:935–943;  http://dx.doi.org/10.1289/ehp.1408581

Address correspondence to R.A. Mooney, 601 Elmwood Ave., Box 608, Rochester, New York, 14642 USA. Telephone: (585) 275-8762. E-mail: robert_mooney@urmc.rochester.edu

We thank S. Mack and K. Maltby for assistance with histology, R. Gelein for bone lead measurements, and M. Thullen for microCT imaging and analysis.

This work was supported by National Institutes of Health (NIH) Public Health Service grants T32 ES07026, T32 AR053459, P01 ES011854, P30 AR061307, and P30 ES301247 and by the AO Trauma Research Fund. J.A.I. is supported by National Science Foundation graduate research fellowship no. 2012116002.

The authors declare they have no actual or potential competing financial interests.

Received: 21 April 2014 Accepted: 8 April 2015 Advance Publication: 10 April 2015 Final Publication: 1 October 2015

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