Da. Fox et al., FUNCTIONAL ALTERATIONS AND APOPTOTIC CELL-DEATH IN THE RETINA FOLLOWING DEVELOPMENTAL OR ADULT LEAD-EXPOSURE, Neurotoxicology, 18(3), 1997, pp. 645-664
Long-term visual system deficits occur in man and animals following de
velopmental and occupational lead exposure. Recent experimental data s
uggests that the adult brain is not altered following lead exposure. T
herefore, the aim of these studies was to use the retina as a CNS mode
l to examine and compare the morphological, biochemical and electroret
inographic (ERG) changes occurring in rats exposed to low or moderate
levels of lead during development (0-21 days of age) with those occurr
ing in adult rats with equivalent blood and retinal levels of lead for
three or six weeks. Five main results were obtained. First, developme
ntal and adult lead exposure for six weeks produced age- and dose-depe
ndent retinal degeneration such that rods and bipolar cells were selec
tively lost. At the ultrastructural level, all dying cells exhibited t
he classical morphological features of apoptotic cell death. Second, i
n the lead-exposed groups, the decrease in the number of rods was corr
elated with the loss of rhodopsin content per eye confirming that rods
were directly affected by lead. Third, single-flash rod ERGs and cone
ERGs obtained from developmentally and adult lead-exposed rats demons
trated that there were age-and dose-dependent decreases in the rod a-w
ave and b-wave sensitivity and maximum amplitudes without any effect o
n cones. In adult rats exposed to lead for three weeks, qualitatively
similar ERG changes occurred in the absence of cell loss or decrease i
n rhodopsin content. Fourth, developmental and adult lead exposure for
three and six weeks produced age-and dose-dependent decreases in reti
nal cGMP phosphodiesterase (PDE) activity resulting in increased cGMP
levels. Fifth, picomolar to micromolar concentration of free lead dire
ctly inhibited rat retinal and purified bovine rod cGMP PDE. In summar
y, there are three main conclusions. First, the retinas of developing
and adult rats exposed to lead exhibit qualitatively similar rod-media
ted ERG alterations as well as rod and bipolar apoptotic cell: death.
Thus, developing and mature retinas are both sensitive to the adverse
effects of lead: albeit to significantly different extents. Second, a
similar biochemical mechanism such as the inhibition of rod and bipola
r cell cGMP PDE, varying only in degree and duration, underlies both t
he lead-induced ERG rod-mediated deficits and the rod and bipolar apop
totic cell death. Third, the composite results from our experiments an
d those of others suggest that the developing retina might be more sen
sitive to preweaning lead exposure than the hippocampus and thus may s
erve as a good model for studying the cellular and molecular mechanism
s underlying developmental and adult lead neurotoxicity. (C) 1997 Into
x Press, Inc.