| Low-Level Human Equivalent Gestational Lead Exposure Produces Supernormal Scotopic Electroretinograms, Increased Retinal Neurogenesis, and Decreased Retinal Dopamine Utilization in Rats Donald A. Fox,1,2,3 Subbarao V. Kala,4 W. Ryan Hamilton,2 Jerry E. Johnson,5 and James P. O'Callaghan6 1College of Optometry, 2Department of Biology and Biochemistry, and 3Department of Pharmacology and Pharmaceutical Sciences, University of Houston, Houston, Texas, USA; 4One Source Toxicology Laboratory, Inc., Pasadena, Texas, USA; 5Department of Natural Sciences, University of Houston-Downtown, Houston, Texas, USA; 6Toxicology and Molecular Biology Branch, Health Effects Research Laboratory, Centers for Disease Control and Prevention-National Institute of Occupational Safety and Health, Morgantown, West Virginia, USA Abstract
Background: Postnatal lead exposure in children and animals produces alterations in the visual system primarily characterized by decreases in the rod-mediated (scotopic) electroretinogram (ERG) amplitude (subnormality) . In contrast, low-level gestational Pb exposure (GLE) increases the amplitude of scotopic ERGs in children (supernormality) . Objectives: The goal of this study was to establish a rat model of human equivalent GLE and to determine dose–response effects on scotopic ERGs and on retinal morphology, biochemistry, and dopamine metabolism in adult offspring. Methods: We exposed female Long-Evans hooded rats to water containing 0, 27 (low) , 55 (moderate) , or 109 (high) ppm of Pb beginning 2 weeks before mating, throughout gestation, and until postnatal day (PND) 10. We measured maternal and litter indices, blood Pb concentrations (BPb) , retinal Pb concentrations, zinc concentrations, and body weights. On PND90, we performed the retinal experiments. Results: Peak BPb concentrations were < 1, 12, 24, and 46 µg/dL in control, low-, moderate- and high-level GLE groups, respectively, at PNDs 0–10. ERG supernormality and an increased rod photoreceptor and rod bipolar cell neurogenesis occurred with low- and moderate-level GLE. In contrast, high-level GLE produced ERG subnormality, rod cell loss, and decreased retinal Zn levels. GLE produced dose-dependent decreases in dopamine and its utilization. Conclusions: Low- and moderate-level GLE produced persistent scotopic ERG supernormality due to an increased neurogenesis of cells in the rod signaling pathway and/or decreased dopamine utilization, whereas high-level GLE produced rod-selective toxicity characterized by ERG subnormality. The ERG is a differential and noninvasive biomarker of GLE. The inverted U-shaped dose–response curves reveal the sensitivity and vulnerability of the developing retina to GLE. Key words: bipolar cells, development, dopamine, electroretinograms, gestation, lead, neurogenesis, rod photoreceptors, scotopic, zinc. Environ Health Perspect 116:618–625 (2008) . doi:10.1289/ehp.11268 available via http://dx.doi.org/ [Online 22 February 2008]
Address correspondence to D.A. Fox, College of Optometry, University of Houston, 4901 Calhoun Rd., Houston, TX 77204–2020, USA. Telephone: (713) 743–1964. Fax: (713) 743–2053. E-mail: dafox@uh.edu We thank M. Gondo for expert technical assistance and L.J. Frishman for valuable discussions and suggestions. This study 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 15 January 2008 ; accepted 21 February 2008. An erratum is posted online at http://www.ehponline.org/docs/2008/11268/errata.html.
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