Cumulative Lead Dose and Cognitive Function in Adults: A Review of Studies That Measured Both Blood Lead and Bone Lead

OBJECTIVE: We review empirical evidence for the relations of recent and cumulative lead dose with cognitive function in adults. DATA SOURCES: A systematic search of electronic databases resulted in 21 environmental and occupational studies from 1996 to 2006 that examined and compared associations of recent (in blood) and cumulative (in bone) lead doses with neurobehavioral outcomes. DATA EXTRACTION: Data were abstracted after consideration of exclusion criteria and quality assessment, and then compiled into summary tables. CONCLUSIONS: At exposure levels encountered after environmental exposure, associations with bio-markers of cumulative dose (mainly lead in tibia) were stronger and more consistent than associations with blood lead levels. Similarly, in studies of former workers with past occupational lead exposure, associations were also stronger and more consistent with cumulative dose than with recent dose (in blood). In contrast, studies of currently exposed workers generally found associations that were more apparent with blood lead levels; we speculate that the acute effects of high, recent dose may mask the chronic effects of cumulative dose. There is moderate evidence for an association between psychiatric symptoms and lead dose but only at high levels of current occupational lead exposure or with cumulative dose in environmentally exposed adults

A possible role for miRNA silencing in disease phenotype variation in Swedish transthyretin V30M carriers

Our results are the first to show the presence of a 3'UTR polymorphism on the V30M haplotype in Swedish carriers, which can serve as a miRNA binding site potentially leading to down-regulated expression from the mutated TTR allele. This finding may be related to the low penetrance and high age at onset of the disease observed in the Swedish patient population

Environmental chemical stressors as epigenome modifiers:a new horizon in assessment of toxicological effects

In eukaryotic cells, chromatin transformation from euchromatin into heterochromatin as a means of controlling gene expression and replication has been known as the ?accessibility hypothesis?. The interplay of epigenetic changes including histone modifications, DNA methylation, RNA interference (RNAi) and other functional epigenetic components are intricate. It is believed that these changes are well-programmed, inherited and can be modified by environmental contaminant stressors. Environmentally-driven epigenetic alterations during development, e.g. embryonic, foetal or neonatal stage, may influence disease susceptibility in adulthood. Therefore, understanding how epigenome modifications develop in response to environmental chemicals and, how epigenetic-xenobiotic interactions influence human health will shed new insights into gene-environment interactions in the epidemiology of several diseases including cancer. In this review, we consider studies of chemical modifiers including nutritional and xenobiotic effects on epigenetic components in vitro or in vivo. By examining the most-studied epigenome modifications and how their respective roles are interlinked, we highlight the central role of xenbiotic-modified epigenetic mechanisms. A major requirement will be to study and understand effects following environmentally-relevant exposures. We suggest that the study of epigenetic toxicology will open up new opportunities to devise strategies for the prevention or treatment of at-risk populations

Electrically stimulated rapid gene expression in the brain: ornithine decarboxylase and c-fos.

A single electroconvulsive shock (ECS) resulted in a major induction of cerebral ornithine decarboxylase (ODC) mRNA and a rapid and transient elevation of ODC enzyme activity. The proto-oncogene c-fos was also transiently induced under the same conditions. Following a rapid rise in mRNA levels, the messages for these proteins take different courses. The c-fos mRNA fell to below control levels by 1 h, while the ODC mRNA remained elevated beyond 24 h. The ECS-induced elevation of ODC enzyme activity was not abolished by adrenalectomy but was attenuated significantly by the anti-convulsant MK-801. These results imply that the induction of cerebral ODC may be neuronal activity dependent, and suggest that the ODC/polyamine system may be linked to the proposed third messenger cascade, involving c-fos, which couples cell stimulation to gene expression, resulting in long-term adaptive responses

Electrically stimulated rapid gene expression in the brain: ornithine decarboxylase and c-fos.

A single electroconvulsive shock (ECS) resulted in a major induction of cerebral ornithine decarboxylase (ODC) mRNA and a rapid and transient elevation of ODC enzyme activity. The proto-oncogene c-fos was also transiently induced under the same conditions. Following a rapid rise in mRNA levels, the messages for these proteins take different courses. The c-fos mRNA fell to below control levels by 1 h, while the ODC mRNA remained elevated beyond 24 h. The ECS-induced elevation of ODC enzyme activity was not abolished by adrenalectomy but was attenuated significantly by the anti-convulsant MK-801. These results imply that the induction of cerebral ODC may be neuronal activity dependent, and suggest that the ODC/polyamine system may be linked to the proposed third messenger cascade, involving c-fos, which couples cell stimulation to gene expression, resulting in long-term adaptive responses

Differential effects of difluoromethylornithine on basal and induced activity of cerebral ornithine decarboxylase and mRNA.

The induction of the activity of cerebral ornithine decarboxylase (EC 4.1.1.17) and mRNA by electrical stimulation exhibits regional differences. The effects of the enzyme inhibitor difluoromethylornithine on these regional variations was examined. Administration of this inhibitor resulted in pronounced depression of both basal and induced activity of ornithine decarboxylase in the hippocampus. Basal activity of the enzyme in the neocortex and the cerebellum appeared to be resistant to difluoromethylornithine but the induced enzyme activity was sensitive to the effects of this inhibitor. Susceptibility to difluoromethylornithine may be directly correlated with a slower turnover rate for ornithine decarboxylase. These results suggest that ornithine decarboxylase in the hippocampus may possess a longer half-life than its counterparts in other regions of the brain. Pretreatment with difluoromethylornithine had no effect on the induced ornithine decarboxylase mRNA in the neocortex. Thus, elevated activity of ornithine decarboxylase enzyme, due to electrical stimulation, appears to not have any effect on either the transcription or the decay rate of the induced ornithine decarboxylase mRNA. These findings support the concept of region-specific regulation of cerebral ornithine decarboxylase

Differential effects of difluoromethylornithine on basal and induced activity of cerebral ornithine decarboxylase and mRNA.

The induction of the activity of cerebral ornithine decarboxylase (EC 4.1.1.17) and mRNA by electrical stimulation exhibits regional differences. The effects of the enzyme inhibitor difluoromethylornithine on these regional variations was examined. Administration of this inhibitor resulted in pronounced depression of both basal and induced activity of ornithine decarboxylase in the hippocampus. Basal activity of the enzyme in the neocortex and the cerebellum appeared to be resistant to difluoromethylornithine but the induced enzyme activity was sensitive to the effects of this inhibitor. Susceptibility to difluoromethylornithine may be directly correlated with a slower turnover rate for ornithine decarboxylase. These results suggest that ornithine decarboxylase in the hippocampus may possess a longer half-life than its counterparts in other regions of the brain. Pretreatment with difluoromethylornithine had no effect on the induced ornithine decarboxylase mRNA in the neocortex. Thus, elevated activity of ornithine decarboxylase enzyme, due to electrical stimulation, appears to not have any effect on either the transcription or the decay rate of the induced ornithine decarboxylase mRNA. These findings support the concept of region-specific regulation of cerebral ornithine decarboxylase