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R. Hamilton, J. E. Johnson, W. Xiao, A. Giddabasappa, S. Chaney, D. B. Miller, J. P. O'Callaghan, M. Wang, L. J. Frishman, D. A. Fox; Dopamine Amacrine Cell (DA AC) Apoptosis and Decreased DA Utilization Occur Without ERG Supernormality in Mice With Gestational Lead Exposure (GLE). Invest. Ophthalmol. Vis. Sci. 2008;49(13):4881.
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© ARVO (1962-2015); The Authors (2016-present)
Prenatal lead exposure produces supernormal scotopic ERGs in children as well as adult rats and monkeys. In the latter two, this correlates with decreased retinal [DA]. Supernormal scotopic ERGs also occur in early drug-free Parkinson’s patients and animals following DA AC loss via 6-OH DA. Previously we reported that GLE increased and prolonged progenitor cell proliferation, increased rods and bipolar cells, and decreased tyrosine hydroxylase positive (TH+ve) DA ACs without affecting other ACs. The goals of this study were to analyze the mode and temporal sequence of DA AC loss, measure retinal [TH] and DA metabolism, and examine scotopic ERGs in GLE mice.
C57BL/6 female mice were exposed to water or lead throughout gestation and until postnatal day (PN10): a period equivalent to human gestation. Confocal studies used fixed-frozen vertical sections and fixed retinal wholemounts from developing and adult mice followed by stereological procedures. In adult retinas, immunoblots measured [TH]; HPLC analyzed [DA], [DOPAC] and [HVA]; DA utilization ([DOPAC]/[DA]) was calculated; and scotopic ERGs were assessed.
In developing GLE retinas, the number of apoptotic (caspase-3+ve) DA ACs was significantly increased and TH+ve labeling of sublamina 1 was decreased. In adult GLE mice, the number of TH+ve cells and density of axons ramifying in sublamina 1 were significantly decreased; [TH] was significantly decreased consistent with the DA AC loss; dark- and light-adapted [DA] was not changed, indicating normal TH activity; and [DOPAC] and [HVA] were significantly decreased, and thus DA utilization was significantly decreased. Unexpectedly, scotopic ERGs were not different from controls.
The decreased DAergic utilization likely resulted from a decreased DA release. The reason for the absence of ERG supernormality in adult GLE mice compared to children, monkeys and rats with GLE exposure is not yet known, however, it appears related to decreased DA utilization. A loss of DA ACs and decreased DAergic utilization during development also could underlie the increased and prolonged proliferation of retinal progenitor cells seen in developing GLE retinas (ARVO 2007).
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