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A. Giddabasappa, W. Xiao, B. Xu, J. E. Johnson, S. Chaney, R. Hamilton, R. Khanna, M. Brooks, A. Swaroop, D. A. Fox; Gestational Lead Exposure Upregulates Cell Cycle Genes and Prolongs Retinal Progenitor Cell (RPC) Proliferation Resulting in Increased Rod Photoreceptor and Bipolar Cells. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5695.
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© ARVO (1962-2015); The Authors (2016-present)
Gestational lead exposure produces supernormal scotopic ERGs in children, monkeys and rodents. Previously we showed that gestational lead exposure produced a dose-dependent increase in the number of late-born retinal neurons (rods and bipolar cells) in adult mouse retina, with no change in the number of Müller glial cells. The aim of this study was to determine the molecular and cellular mechanisms underlying the novel retinal phenotype produced by low-level gestational lead exposure.
Female C57BL/6 mice were exposed to tap water or a solution containing a low level of lead acetate throughout pregnancy and until postnatal day 10 (PN10): a period equivalent to the human gestation period. Microarray studies were conducted on E16.5, E18.5, PN2, PN6 and PN10 retinas using the Affymetrix GeneChip® Mouse Genome 430 2.0 Array. Results were validated by quantitative real-time PCR (qPCR) and extended with SuperArray’s cell cycle qPCR array. Immunocytochemical and confocal studies examined selected cell cycle and RPC markers. Cell counts were obtained using stereological techniques.
Functional classification of the microarray results revealed the up-regulation of several cell cycle genes. Q-PCR studies confirmed these microarray results. The qPCR array extended these results to reveal the up-regulation of Ccnd1, Ccne1, Ccna1, Ccna2 and Ccnb1 as well as the down-regulation of several negative cell cycle regulator genes. Immunocytochemical and confocal studies showed that developing retinas from mice with gestational lead exposure had an increased number and prolonged expression of Ki67-, BrdU-, PH3- and cyclin D1-positive RPCs.
Low-level gestational lead exposure produced a novel retinal phenotype characterized by a selective increase in late-born retinal neurons. Microarray and qPCR studies showed that gestational lead exposure up-regulated cell cycle genes. Immunocytochemical and confocal studies confirmed and extended these results to reveal an increased and prolonged proliferation of RPCs. These findings show that gestational lead exposure targets molecular sites in the developing retina that regulate RPC proliferation and neurogenesis. The mechanism underlying the selective increase in the number of late-born RPCs that differentiate into rod photoreceptors and bipolar cells is under investigation.
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