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Q. Chen, J. Johnson, A. Giddabasappa, W. Xiao, M. Gondo, D.A. Fox; Gestational Lead Exposure Switches Cell Fate Specification and Increases Proliferation in the Developing Mouse Retina . Invest. Ophthalmol. Vis. Sci. 2005;46(13):589.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Gestational lead (Pb) exposure produces supernormal scotopic ERG a– and b–waves in children, monkeys and rats. The sites and mechanisms underlying these novel ERG findings are unknown. Our goal was to use our clinically relevant mouse model of gestational Pb exposure to determine the effects of Pb on the morphological and immunohistochemical development of the retina. Methods: Female C57BL/6 mice were exposed to tap water or one of two different Pb solutions two weeks prior to mating, throughout pregnancy and until postnatal day 10 (PN10): equivalent to human gestation period. Blood Pb concentrations [BPb] and retinas were obtained at different prenatal and postnatal times. Light and electron microscopy were used to identify and count rods, cones and inner retinal cells. Fixed retinas were processed for vertical cryostat sections or retinal whole mounts, stained with different and specific retinal cell markers, and examined using epifluorescent and laser scanning confocal microscopy. Results:At PN10, the mean [BPb] in controls and lead groups were <1, 10 and 22 µg/dL, while at PN60 all values were similar (∼1 µg/dL). At PN60, morphology and nuclear dye staining studies revealed a Pb–dependent increase in the total number of cells in the outer and inner nuclear layers: rods, bipolar cells (BCs) and Muller glial cells (MCs). In the same Pb–treated mice there was a small decrease in cones and horizontal cells (HCs) with no obvious change in amacrine cells (ACs). Correspondingly, there was increased expression of rhodopsin (rods), Chx10 (mostly BCs), PKC alpha (rod BCs), and cyclin D3 and glutamine synthetase (MCs) in retinas of Pb–exposed mice starting from PN10. In PN60 retinas from Pb–exposed mice, the expression of M–opsin (cone photoreceptors) and calbindin (HCs) were decreased, whereas the expression of disabled–1 (AII glycinergic ACs), glutamate decarboxylase 65 (GABA ACs) and choline acetyltransferase (cholinergic ACs) in these retinas were not changed. Conclusions:Low–level gestational Pb exposure in mice produced pleiotropic effects. That is, Pb apparently switched the cell fate of many of the early–born to late–born retinal progenitors and also increased the proliferation of the late–born progenitors. The timing and molecular mechanisms underlying the presumed Pb–induced change in neuronal and glial competency are not yet known. Our future work will focus on both intrinsic regulators and external signals. These results suggest that the Pb–induced supernormal scotopic ERGs likely result from an increased number of cells in the rod–mediated signal pathway.
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