Calcium overload is suggested to play a fundamental role in the process of rod apoptosis in chemical-induced and inherited retinal degenerations. However, this hypothesis has not been tested directly. We developed an in vitro model utilizing isolated rat retinas to determine the mechanisms underlying Ca Apoptosis is an active mode of cell death that is induced by a variety of physiological and pathological stimuli. Convergent evidence suggests that mitochondria and caspases play a central and fundamental role in the effector or executioner phase of apoptosis (1). Early during the effector phase, the mitochondrial permeability transition pore (PTP), 1 a megachannel in the inner mitochondrial membrane, is opened by a variety of apoptotic inducers such as elevated matrix Ca 2ϩ , pro-oxidants, and thiol-reactive agents (1-3). This leads to mitochondrial depolarization (decrease in ⌬⌿ m ) and subsequently to the release of cytochrome c and/or apoptosis-inducing factor from mitochondria to cytosol or nuclei (1, 4, 5). Caspases are activated, which cleave downstream death substrates and activate endonucleases that cleave genomic DNA into fragments resulting in the apoptotic nuclear morphology (6, 7). The opening of the mitochondrial PTP and the apoptotic process can be inhibited by a diverse group of agents such as Bcl-2, Bcl-x L , bongkrekic acid, and CsA (1).Sustained increases in intracellular [Ca 2ϩ ] trigger apoptosis in a diverse array of in vivo and in vitro systems (1, 8). Results from several studies suggest that elevated rod photoreceptor [Ca 2ϩ ] plays a key role in the process of apoptotic rod cell death in humans and animals during inherited retinal degenerations, retinal diseases and injuries, and chemical exposure. These include patients with retinitis pigmentosa and cancer-associated retinopathy (9, 10), lead-exposed rats (11-13), retinal degeneration mice (13,14), rats injected with anti-recoverin monoclonal antibodies (15), rats with hypoxic-ischemic injury (16), and rats with light induced damage (17).Several neurotoxic heavy metals, transition metals, and organometals produce neuronal apoptosis in whole animals and cultured cells (11, 12, 18 -25). For example, low to moderate level Pb 2ϩ exposure produces apoptotic rod and bipolar cell death in developing and adult rats (11,12) and apoptotic neuronal cell death in primary cultured cells (23,24). Similarly, Cu 2ϩ and methyl mercury produce apoptosis in the developing and mature olfactory epithelium and cerebellum, respectively (18,22). Although the molecular mechanisms underlying the apoptosis induced by these different metals are unknown, there are two possible, though not mutually exclusive, triggering mechanisms: one is Ca 2ϩ overload and the other is the generation of ROS. Both in vivo and in vitro lead exposure increase rod and retinal intracellular [Ca 2ϩ ] during cell death (26, 27). Hg 2ϩ , tributyltin, and methyl mercury also cause Ca 2ϩ overload in cultured neuronal cells prior to cell death (19,20,28). Moreover, Hg 2ϩ , Mn 2ϩ , Cu 2ϩ...

BackgroundLow-level developmental lead exposure is linked to cognitive and neurological disorders in children. However, the long-term effects of gestational lead exposure (GLE) have received little attention.ObjectivesOur goals were to establish a murine model of human equivalent GLE and to determine dose–response effects on body weight, motor functions, and dopamine neurochemistry in year-old offspring.MethodsWe exposed female C57BL/6 mice to water containing 0, 27 (low), 55 (moderate), or 109 ppm (high) of lead from 2 weeks prior to mating, throughout gestation, and until postnatal day 10 (PN10). Maternal and litter measures, blood lead concentrations ([BPb]), and body weights were obtained throughout the experiment. Locomotor behavior in the absence and presence of amphetamine, running wheel activity, rotarod test, and dopamine utilization were examined in year-old mice.ResultsPeak [BPb] were < 1, ≤ 10, 24–27, and 33–42 μg/dL in control, low-, moderate- and high-dose GLE groups at PN0–10, respectively. Year-old male but not female GLE mice exhibited late-onset obesity. Similarly, we observed male-specific decreased spontaneous motor activity, increased amphetamine-induced motor activity, and decreased rotarod performance in year-old GLE mice. Levels of dopamine and its major metabolite were altered in year-old male mice, although only forebrain utilization increased. GLE-induced alterations were consistently larger in low-dose GLE mice.ConclusionsOur novel results show that GLE produced permanent male-specific deficits. The nonmonotonic dose-dependent responses showed that low-level GLE produced the most adverse effects. These data reinforce the idea that lifetime measures of dose–response toxicant exposure should be a component of the neurotoxic risk assessment process.

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