| Low-Level Human Equivalent Gestational Lead Exposure Produces Sex-Specific Motor and Coordination Abnormalities and Late-Onset Obesity in Year-Old Mice J. Leigh Leasure,1,2 Anand Giddabasappa,2,3 Shawntay Chaney,2,3 Jerry E. Johnson Jr.,3,4 Konstantinos Pothakos,5 Yuen Sum Lau,5 and Donald A. Fox2,3,5 1Department of Psychology, 2Department of Biology and Biochemistry, and 3College of Optometry, University of Houston, Houston, Texas, USA; 4Department of Natural Sciences, University of Houston-Downtown, Houston, Texas, USA; 5Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Texas, USA Abstract
Background: Low-level developmental lead exposure is linked to cognitive and neurological disorders in children. However, the long-term effects of gestational lead exposure (GLE) have received little attention. Objectives: Our goals were to establish a murine model of human equivalent GLE and to determine dose–response effects on body weight, motor functions, and dopamine neurochemistry in year-old offspring. Methods: We exposed female C57BL/6 mice to water containing 0, 27 (low) , 55 (moderate) , or 109 ppm (high) of lead from 2 weeks prior to mating, throughout gestation, and until postnatal day 10 (PN10) . Maternal and litter measures, blood lead concentrations ([BPb]) , and body weights were obtained throughout the experiment. Locomotor behavior in the absence and presence of amphetamine, running wheel activity, rotarod test, and dopamine utilization were examined in year-old mice. Results: Peak [BPb] were < 1, ≤ 10, 24–27, and 33–42 µg/dL in control, low-, moderate- and high-dose GLE groups at PN0–10, respectively. Year-old male but not female GLE mice exhibited late-onset obesity. Similarly, we observed male-specific decreased spontaneous motor activity, increased amphetamine-induced motor activity, and decreased rotarod performance in year-old GLE mice. Levels of dopamine and its major metabolite were altered in year-old male mice, although only forebrain utilization increased. GLE-induced alterations were consistently larger in low-dose GLE mice. Conclusions: Our novel results show that GLE produced permanent male-specific deficits. The nonmonotonic dose-dependent responses showed that low-level GLE produced the most adverse effects. These data reinforce the idea that lifetime measures of dose–response toxicant exposure should be a component of the neurotoxic risk assessment process. Key words: aging, amphetamine, balance, dopamine, fetal, sex, gestation, lead, motor activity, obesity. Environ Health Perspect 116:355–361 (2008) . doi:10.1289/ehp.10862 available via http://dx.doi.org/ [Online 7 December 2007]
Address correspondence to D.A. Fox, University of Houston, College of Optometry, 4901 Calhoun Rd., Houston, TX 77204-2020 USA. Telephone: (713) 743-1964. Fax: (713) 743-2053. E-mail: dafox@uh.edu This research was funded by National Institutes of Health grants RO1 ES012482, P30 EY07751, and T32 EY07024. The authors declare they have no competing financial interests. Received 7 September 2007 ; accepted 7 December 2007.
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