Lead Exposure Affects Levels of Galactolipid Metabolic Enzymes in the Developing Rat Brain

Deng, Wenbin; Poretz, R. D.

doi:10.1006/taap.2001.9142

Cited by 34 publications

(14 citation statements)

References 33 publications

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“…These experiments were conducted entirely with MeHg for several reasons. First, there is already extensive evidence that Pb exposure in vivo has adverse effects on myelination and on O-2A/OPCs (e.g., [38,43,53,139–142]). In contrast, evidence that MeHg exposure may have any effects on myelination thus far comes only from observations of increased latencies in ABRs [75–79], with no studies examining effects of this toxicant on the function of cells important for myelination (i.e., oligodendrocytes or their ancestral O-2A/OPCs).…”

Section: Resultsmentioning

confidence: 99%

Chemically Diverse Toxicants Converge on Fyn and c-Cbl to Disrupt Precursor Cell Function

Dong

Pröschel

et al. 2007

PLoS Biol

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Identification of common mechanistic principles that shed light on the action of the many chemically diverse toxicants to which we are exposed is of central importance in understanding how toxicants disrupt normal cellular function and in developing more effective means of protecting against such effects. Of particular importance is identifying mechanisms operative at environmentally relevant toxicant exposure levels. Chemically diverse toxicants exhibit striking convergence, at environmentally relevant exposure levels, on pathway-specific disruption of receptor tyrosine kinase (RTK) signaling required for cell division in central nervous system (CNS) progenitor cells. Relatively small toxicant-induced increases in oxidative status are associated with Fyn kinase activation, leading to secondary activation of the c-Cbl ubiquitin ligase. Fyn/c-Cbl pathway activation by these pro-oxidative changes causes specific reductions, in vitro and in vivo, in levels of the c-Cbl target platelet-derived growth factor receptor-α and other c-Cbl targets, but not of the TrkC RTK (which is not a c-Cbl target). Sequential Fyn and c-Cbl activation, with consequent pathway-specific suppression of RTK signaling, is induced by levels of methylmercury and lead that affect large segments of the population, as well as by paraquat, an organic herbicide. Our results identify a novel regulatory pathway of oxidant-mediated Fyn/c-Cbl activation as a shared mechanism of action of chemically diverse toxicants at environmentally relevant levels, and as a means by which increased oxidative status may disrupt mitogenic signaling. These results provide one of a small number of general mechanistic principles in toxicology, and the only such principle integrating toxicology, precursor cell biology, redox biology, and signaling pathway analysis in a predictive framework of broad potential relevance to the understanding of pro-oxidant–mediated disruption of normal development.

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Section: Resultsmentioning

confidence: 99%

Chemically Diverse Toxicants Converge on Fyn and c-Cbl to Disrupt Precursor Cell Function

Dong

Pröschel

et al. 2007

PLoS Biol

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“…Altered fatty acid composition of erythrocyte membranes has also been demonstrated in chronic lead exposure [5,10,11]. It has also been demonstrated that lead exposure affects levels of galactolipid metabolic enzymes in the developing rat brain resulting in myelin defects [3]. All these observations are largely more suggestive than conclusive about lead-induced alterations in lipid metabolism.…”

Section: Introductionmentioning

confidence: 99%

Plasma lipid profiles and risk of cardiovascular disease in occupational lead exposure in Abeokuta, Nigeria

et al. 2005

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In order to investigate the effects of lead exposure on risk of cardiovascular disease during occupational exposure to this metal, plasma cholesterol and its fractions as high-density liporotein (HDL), low-density liporotein (LDL) and triglyceride were determined in various artisans in Abeokuta, Nigeria who have been shown to be occupationally exposed to lead and these were related to blood lead levels. Increased risk of cardiovascular disease was observed in the artisans. Total cholesterol in the artisans was between 1.5 and 2.0 times higher in the artisans than that present in controls while LDL cholesterol was between 1.6 and 2.4 times higher in the artisans when compared with control subjects [p < 0.001]. HDL cholesterol and triglyceride levels were not affected [p > 0.05]. A significant positive correlation was observed between blood lead and total cholesterol on one hand [r = 0.372; p = 3.0 × 10 -5 ] and blood lead and LDL cholesterol on the other hand [r = 0.283; p = 0.001]. LDL/HDL cholesterol ratio was also higher in the artisans when compared with control. Blood pressure (systolic and diastolic) and other anthropometric parameters were not significantly different between the artisans and the control subjects [p > 0.05]. Results suggest that lead exposure increases cholesterol synthesis and transport to peripheral tissues whereas reverse cholesterol transport to the liver is not affected.

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“…In fetal guinea pigs gestationally exposed to lead through the dam's drinking water, the activity of glycerol phosphate dehydrogenase, a developmental marker of oligodendroglia, was reduced at gestation day 22 with blood lead levels of 10-30 mg dl À1 . Another study in rats chronically exposed to lead during gestation and lactation and after the weaning through drinking water (0.2% lead acetate) reported that lead decreased the levels of galactolipids, the activities of galactolipid metabolic enzymes, and the cellular activities of 29,39-cyclic nucleotide 39-phosphohydrolase (CNPase), another oligodendrocyte marker in the brain (Deng and Poretz 2001b), suggesting a delayed oligodendrogliogenesis. However, animals with these changes had moderate to high blood lead levels (60-240 mg dl À1 ) (Deng and Poretz 2001b), and brains could be estimated to have at least 600-2400 ppm lead according to brain lead level in proportion to blood lead level (Bradbury and Deane 1993).…”

Section: 25232(ii) Myelinating Cells Myelinating Cells Include Smentioning

confidence: 99%

“…Another study in rats chronically exposed to lead during gestation and lactation and after the weaning through drinking water (0.2% lead acetate) reported that lead decreased the levels of galactolipids, the activities of galactolipid metabolic enzymes, and the cellular activities of 29,39-cyclic nucleotide 39-phosphohydrolase (CNPase), another oligodendrocyte marker in the brain (Deng and Poretz 2001b), suggesting a delayed oligodendrogliogenesis. However, animals with these changes had moderate to high blood lead levels (60-240 mg dl À1 ) (Deng and Poretz 2001b), and brains could be estimated to have at least 600-2400 ppm lead according to brain lead level in proportion to blood lead level (Bradbury and Deane 1993). In rat pups lactationally exposed to lead through the dam's drinking water (0.2% lead acetate), lead altered the developmental profiles of the proteolipid protein (PLP) and MBP, two major structural constituents of the central nervous system myelin, but not CNPase at PND 20 when animal brains had lead levels of 0.20 mg g À1 tissue (200 ppm) (Zawia and Harry 1995), suggesting that lead at this level induced changes in myelin structure but not in oligodendroglial number.…”

Section: 25232(ii) Myelinating Cells Myelinating Cells Include Smentioning

confidence: 99%

Heavy Metal-Regulated Gene Expression

Qian

2010

Comprehensive Toxicology

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Lead Exposure Affects Levels of Galactolipid Metabolic Enzymes in the Developing Rat Brain

Cited by 34 publications

References 33 publications

Chemically Diverse Toxicants Converge on Fyn and c-Cbl to Disrupt Precursor Cell Function

Chemically Diverse Toxicants Converge on Fyn and c-Cbl to Disrupt Precursor Cell Function

Plasma lipid profiles and risk of cardiovascular disease in occupational lead exposure in Abeokuta, Nigeria

Heavy Metal-Regulated Gene Expression

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