Low-Level Human Equivalent Gestational Lead Exposure Produces Supernormal Scotopic Electroretinograms, Increased Retinal Neurogenesis, and Decreased Retinal Dopamine Utilization in Rats

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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.

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Most cited references 55

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Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter.

Richard Canfield, Charles R. Henderson, Deborah A. Cory-Slechta … (2003)

Despite dramatic declines in children's blood lead concentrations and a lowering of the Centers for Disease Control and Prevention's level of concern to 10 microg per deciliter (0.483 micromol per liter), little is known about children's neurobehavioral functioning at lead concentrations below this level. We measured blood lead concentrations in 172 children at 6, 12, 18, 24, 36, 48, and 60 months of age and administered the Stanford-Binet Intelligence Scale at the ages of 3 and 5 years. The relation between IQ and blood lead concentration was estimated with the use of linear and nonlinear mixed models, with adjustment for maternal IQ, quality of the home environment, and other potential confounders. The blood lead concentration was inversely and significantly associated with IQ. In the linear model, each increase of 10 microg per deciliter in the lifetime average blood lead concentration was associated with a 4.6-point decrease in IQ (P=0.004), whereas for the subsample of 101 children whose maximal lead concentrations remained below 10 microg per deciliter, the change in IQ associated with a given change in lead concentration was greater. When estimated in a nonlinear model with the full sample, IQ declined by 7.4 points as lifetime average blood lead concentrations increased from 1 to 10 microg per deciliter. Blood lead concentrations, even those below 10 microg per deciliter, are inversely associated with children's IQ scores at three and five years of age, and associated declines in IQ are greater at these concentrations than at higher concentrations. These findings suggest that more U.S. children may be adversely affected by environmental lead than previously estimated. Copyright 2003 Massachusetts Medical Society

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Comparative aspects of the brain growth spurt.

J Dobbing, Barbara J Sands (1979)

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Timing and topography of cell genesis in the rat retina.

D Rapaport, Douglas Yasumura, D. Wood … (2004)

To understand the mechanisms of cell fate determination in the vertebrate retina, the time course of the generation of the major cell types needs to be established. This will help define and interpret patterns of gene expression, waves of differentiation, timing and extent of competence, and many of the other developmental processes involved in fate acquisition. A thorough retinal cell "birthdating" study has not been performed for the laboratory rat, even though it is the species of choice for many contemporary developmental studies of the vertebrate retina. We investigated the timing and spatial pattern of cell genesis using 3H-thymidine (3H-TdR). A single injection of 3H-TdR was administered to pregnant rats or rat pups between embryonic day (E) 8 and postnatal day (P) 13. The offspring of prenatally injected rats were delivered and all animals survived to maturity. Labeled cells were visualized by autoradiography of retinal sections. Rat retinal cell genesis commenced around E10, 50% of cells were born by approximately P1, and retinogenesis was complete near P12. The first postmitotic cells were found in the retinal ganglion cell layer and were 9-15 microm in diameter. This range includes small to medium diameter retinal ganglion cells and large displaced amacrine cells. The sequence of cell genesis was established by determining the age at which 5, 50, and 95% of the total population of cells of each phenotype became postmitotic. With few exceptions, the cell types reached these developmental landmarks in the following order: retinal ganglion cells, horizontal cells, cones, amacrine cells, rods, bipolar cells, and Müller glia. For each type, the first cells generated were located in the central retina and the last cells in the peripheral retina. Within the sequence of cell genesis, two or three phases could be detected based on differences in timing, kinetics, and topographic gradients of cell production. Our results show that retinal cells in the rat are generated in a sequence similar to that of the primate retina, in which retinogenesis spans more than 100 days. To the extent that sequences reflect underlying mechanisms of cell fate determination, they appear to be conserved. Copyright 2004 Wiley-Liss, Inc.

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Author and article information

Journal

Journal ID (nlm-ta): Environ Health Perspect

Title: Environmental Health Perspectives

Publisher: National Institute of Environmental Health Sciences

ISSN (Print): 0091-6765

Publication date (Print): May 2008

Publication date (Electronic): 22 February 2008

Volume: 116

Issue: 5

Pages: 618-625

Affiliations

[1 ]College of Optometry

[2 ]Department of Biology and Biochemistry and

[3 ]Department of Pharmacology and Pharmaceutical Sciences, University of Houston, Houston, Texas, USA

[4 ]One Source Toxicology Laboratory, Inc., Pasadena, Texas, USA

[5 ]Department of Natural Sciences, University of Houston-Downtown, Houston, Texas, USA

[6 ]Toxicology 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

Author notes

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@ 123456uh.edu

The authors declare they have no competing financial interests.

Article

Publisher ID: ehp0116-000618

DOI: 10.1289/ehp.11268

PMC ID: 2367685

PubMed ID: 18470321

SO-VID: aa87953c-5940-40c8-b3e9-c9d24e65586a

Copyright © This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.

Low-Level Human Equivalent Gestational Lead Exposure Produces Supernormal Scotopic Electroretinograms, Increased Retinal Neurogenesis, and Decreased Retinal Dopamine Utilization in Rats

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Abstract

Background

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Conclusions

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Tobacco Prevention & Cessation

Most cited references 55

Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter.

Comparative aspects of the brain growth spurt.

Timing and topography of cell genesis in the rat retina.

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