Lead-induced alterations of apoptosis and neurotrophic factor mRNA in the developing rat cortex, hippocampus, and cerebellum

Department of Natural Sciences, Fayetteville State University, Fayetteville, NC 28301, USA.
Journal of Biochemical and Molecular Toxicology (Impact Factor: 1.93). 10/2007; 21(5):265-72. DOI: 10.1002/jbt.20191
Source: PubMed


Previous reports have recently shown the prototypic neurotoxicant, lead, to induce apoptosis in the brains of developing organisms. In the current study, timed-pregnant rats were exposed to lead acetate (0.2% in the drinking water) 24 h following birth at postnatal day 1 (PND 1). Dams and pups were continuously exposed to lead through the drinking water of the dam until PND 20. Postnatal exposure in the pups resulted in altered mRNA levels of the following apoptotic and neurotrophic factors: caspase 2 and 3, bax, bcl-x, brain-derived neurotrophic factor (BDNF). Ribonuclease protection assays were conducted to measure the factors simultaneously at the following postnatal time points: 9, 12, 15, 20, 25, days. Our results suggest a brain region- and time-specific response following lead acetate exposure. The region most vulnerable to alterations occurs in the hippocampus with alterations beginning at PND 12, in which caspase 3, bcl-x, BDNF increase with lead exposure. Significant treatment effects were not observed for both the cortex and cerebellum.

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    • "Animal studies show that hippocampus including limbic system, prefrontal cerebral cortex and cerebellum are the principal sites of lead's detrimental effects (Finkelstein et al., 1998). Pb-induced apoptosis has been demonstrated in cultured cerebellar granule cells (Chao et al., 2007; Oberto et al., 1996). High level of developmental Pb exposure in rat pups causes weight loss and growth impairment, with severe deficits in neuromotor development (Luthman et al., 1992; McClain & Becker, 1972; Rosenblum & Johnson, 1968). "
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    ABSTRACT: Studies in urban children exposed to low lead (Pb) have shown neurobehavioral deficits in the domains of intelligence, reaction time and attention. The structures - hippocampus (vital for learning and memory) and cerebellum (play a role in motor behavior and cognition) - which develop postnatally, are affected by developmental Pb exposure. The effect of low level of Pb exposure during specific periods of early brain development on early neurobehavioral outcomes in rat pups has not been studied. So in this study, pregnant albino Wistar strain rats were exposed to low levels of Pb in drinking water during gestation period (G group), lactation period (L group), both gestation and lactation period (GL group) and prior to pregnancy (a period of 1 month) (PG group). The rat pups born in each of these groups were assessed in preweaning neurobehavioral parameters including surface righting reflex, swimming development, negative geotaxis and ascending wire mesh test. The swimming development scores were low in the GL group of rats. The negative geotaxis score in GL and G groups were altered. The day of achievement of ascending wire mesh test was significantly delayed in GL, G and L groups of rats. To conclude, results show that (a) low level of Pb exposure during gestation and lactation period of brain development causes significant alterations in the early neurobehavioral and sensorimotor reflex development in the absence of concomitant weight loss and (b) gestation period only and lactation period only, Pb exposure causes alteration in some of the neurobehavioral outcomes.
    Drug and Chemical Toxicology 09/2015; DOI:10.3109/01480545.2015.1082136 · 1.23 Impact Factor
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    • "There are evidences to suggest that Pb exposure during this period alters this process of normal developmental apoptosis. According to Chao et al. (2007), rats exposed to Pb acetate in the drinking water from postnatal day 1 to 20 showed altered messenger RNA concentration of apoptotic and neurotrophic factors namely caspase 2 and 3, Bax, Bcl-x, and brainderived neurotrophic factor in the hippocampus. So it can be said that the above mechanism might be the one responsible for degeneration of hippocampal neurons observed in the present study. "
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    ABSTRACT: Neuropsychological studies in children who are exposed to lead during their early brain development have shown to develop behavioural and cognitive deficit. The aim of the present study was to assess the cellular damage in hippocampus, amygdala and cerebellum of rat pups exposed to lead during different periods of early brain development. Five groups of rat pups were investigated. (a) Control group (n = 8) (mothers of these rats were given normal drinking water throughout gestation and lactation), (b) pregestation lead-exposed group (n = 8) (mothers of these rats were exposed to 0.2% lead acetate in the drinking water for one month before conception), (c) gestation lead-exposed group (n = 8) (exposed to 0.2% lead acetate in the drinking water through the mother throughout gestation [gestation day 01 to day 21]), (d) lactation lead-exposed group (n = 8) (exposed to 0.2% lead acetate in the drinking water through the mother throughout lactation [postnatal day 01 to day 21]) and (e) gestation and lactation lead-exposed group (n = 8) (exposed to 0.2% lead acetate throughout gestation and lactation). On postnatal day 30, rat pups of all the groups were killed. Numbers of surviving neurons in the hippocampus, amygdala and cerebellum regions were counted using cresyl violet staining technique. Histological data indicate that lead exposure caused significant damage to neurons of hippocampus, amygdala and cerebellum regions in all lead-exposed groups except lactation lead-exposed group. The extent of damage to neurons of hippocampus, amygdala and cerebellum regions in lactation lead-exposed group was comparable to gestation and lactation groups even though the duration of lead exposure was much less in lactation lead-exposed group. To conclude, the postnatal period of brain development seems to be more vulnerable to lead neurotoxicity compared to prenatal period of brain development.
    Toxicology and Industrial Health 08/2014; DOI:10.1177/0748233714545624 · 1.86 Impact Factor
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    • "Another study has also indicated that lead produce rod photoreceptor cell apoptosis by opening the mitochondrial permeability transition pore (He et al. 2000a, b). The effects of lead on apoptosis of cells from hippocampus have been reported previously (Han et al. 2007; Chao et al. 2007; Zhang et al. 2004; Niu et al. 2002), but the design of the present study was different. Another important aspect of lead neurotoxicity to investigate is the sensitivity of younger compare to older rats to lead neurotoxicity. "
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    ABSTRACT: Despite reduction in environmental lead, chronic lead exposure still possess a public health hazard, particularly in children, with devastating effects on developing CNS. To investigate the mechanism of this neurotoxicity, young and adult rats were used to study whether exposure to 500 ppm concentrations of lead could induce apoptosis in hippocampus. 2-4 and 12-14-week-old rats received lead acetate in concentration of 500 ppm for 40 days. Control animals received deionized distilled water. In lead-treated groups, the blood lead levels were increased by 3-4 folds. Light and electron microscopical study of hippocampus revealed increased apoptotic cells. Western blot analysis of Bax and Bcl-2 (pro- and anti-apoptotic gene products, respectively) indicated higher expression of Bax protein and no significant change in bcl-2 expression and accordingly increased the Bax/Bcl-2 ratio compared to control group, confirming the histological study. In conclusion, these data suggest that neurotoxicity of chronic lead exposure in hippocampus in vivo may partly be due to facilitation of apoptosis.
    Cellular and Molecular Neurobiology 02/2010; 30(5):769-74. DOI:10.1007/s10571-010-9504-1 · 2.51 Impact Factor
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