Low-Level Human Equivalent Gestational Lead Exposure Produces Sex-Specific Motor and Coordination Abnormalities and Late-Onset Obesity in Year-Old Mice
- 1 March 2008
- journal article
- Published by Environmental Health Perspectives in Environmental Health Perspectives
- Vol. 116 (3), 355-361
- https://doi.org/10.1289/ehp.10862
Abstract
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. 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. 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. 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. 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.Keywords
This publication has 75 references indexed in Scilit:
- A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult ObesityScience, 2007
- C57BL/6J mice exhibit reduced dopamine D3 receptor-mediated locomotor-inhibitory function relative to DBA/2J miceNeuroscience, 2006
- Fetal Lead Exposure at Each Stage of Pregnancy as a Predictor of Infant Mental DevelopmentEnvironmental Health Perspectives, 2006
- A rationale for lowering the blood lead action level from 10 to 2μg/dLNeuroToxicology, 2006
- Overweight, obesity and cancer: epidemiological evidence and proposed mechanismsNature Reviews Cancer, 2004
- Prenatal lead exposure, delta-aminolevulinic acid, and schizophrenia.Environmental Health Perspectives, 2004
- Associations of blood lead, dimercaptosuccinic acid-chelatable lead, and tibia lead with polymorphisms in the vitamin D receptor and [delta]-aminolevulinic acid dehydratase genes.Environmental Health Perspectives, 2000
- U‐Shaped dose‐response curves: Their occurrence and implications for risk assessmentJournal of Toxicology and Environmental Health, 1990
- Possible involvement of a hypothalamic dopaminergic receptor in development of genetic obesity in miceBiochimica et Biophysica Acta (BBA) - General Subjects, 1986
- Developmental delays in exploration and locomotor activity in male rats exposed to low level leadLife Sciences, 1980