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S. Chaney, R. Hao, J. E. Johnson, Jr., R. Hamilton, S. Mukherjee, W. Xiao, D. A. Fox; Gestational Lead Exposure (GLE) Enhanced Age-Related Retinal Degeneration and Outer Plexiform Layer (OPL) Remodeling. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2237. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
GLE increases retinal progenitor cell proliferation and the number of rods and bipolar cells in adult (2 months old: 2m) mice. However, by 12-15m, GLE retinas compared to age-matched controls have thinner outer (ONL) and inner nuclear layers (INL), a decreased number of Chx10-immunoreactive (IR) bipolar cells (BC), and no change in the number of cones (ARVO 2009). Our goal was to characterize further the specificity of retinal cell loss and examine OPL remodeling in 15m control and GLE retinas.
C57BL/6 female mice were exposed to water or a 55 ppm lead solution throughout gestation and until postnatal day 10: equivalent to human gestation period. Fixed-frozen vertical sections from central retina of 2, 12 and 15m animals were labeled with DRAQ5 (nuclear stain) and anti-rhodopsin, -Chx10, -PKCα (rod BCs) and -cyclin D3 (CyD3: Müller glial nuclei) antibodies and processed for confocal studies and image analysis. Western blots determined whole retinal protein levels of rhodopsin, Chx10, PKCα, CyD3 and glutamine synthetase (GS) for 2, 12 and 15m control and GLE mice. Confocal studies using 15m control and GLE retinas examined OPL remodeling and BC sprouting using anti-PKCα, -plasma membrane calcium-ATPase (PMCA: labels rod spherules), -vesicular glutamate transporter 1 (VGluT1) and -M-cone arrestin (M-CAr) antibodies.
In controls, the ONL and INL thickness decreased from 2 to 12-15m. In 12-15m GLE retinal sections, relative to age-matched controls, the thickness of the rhodopsin-IR ONL decreased and number of PKCα-IR cells decreased, whereas the number of CyD3-IR Müller glial cells was not significantly different. Western blot analyses in 12-15m GLE retinas, relative to age-matched controls, revealed that rhodopsin, Chx10, PKCα and GS protein levels decreased. In 15m GLE retinas, relative to age-matched controls, the number of M-CAr-IR cone pedicles was not significantly different, whereas the number of ectopic BCs sprouting into the ONL increased and the OPL was disorganized and thinned.
These results reveal that GLE enhanced age-related retinal degeneration and OPL remodeling. We postulate that the increased aerobic metabolic demand in GLE retinas resulting from the 25-30% increase in rods and BCs is not sustainable during aging and that this results in selective and enhanced apoptotic cell death and synaptic layer remodeling in the rod-mediated pathway. These findings suggest that children with GLE have an increased risk for age-related retinal degeneration and visual disturbances.
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