Lead exposure-induced cognitive impairment through RyR-modulating intracellular calcium signaling in aged rats.

Lead is widely distributed in the environment and has become a global public health issue. It is well known that lead exposure induces not only neurodevelopmental toxicity but also neurodegenerative diseases, with learning and memory impairment in the later stage. However, the molecular mechanisms remain elusive. The present study investigated the effects of early life and lifetime lead exposure on cognition and identified the molecular mechanisms involved in aged rats. The results herein demonstrated that the lead concentration in peripheral blood and brain tissues in aged rats was significantly increased in a lead dose-dependent manner. High-dose lead exposure caused cognitive functional impairment in aged rats, concomitant with a longer escape latency and a lower frequency of crossing the platform via Morris water maze testing compared to those in the control and low-dose lead exposure groups. Importantly, neuron functional defects were still observed even in early life lead exposure during the prenatal and weaning periods in aged rats. The neurotoxicity induced by lead exposure was morphologically evidenced by a recessed nuclear membrane, a swollen endoplasmic reticulum, and mitochondria in the neurons. Mechanistically, the exposure of aged rats to lead resulted in increasing free calcium concentration, reactive oxygen species, and apoptosis in the hippocampal neurons. Lead exposure increased RyR3 expression and decreased the levels of p-CaMKIIα/CaMKIIα and p-CREB/CREB in the hippocampus of aged rats. These findings indicated that early life lead exposure-induced cognition disorder was irreversible in aged rats. Lead-induced neurotoxicity might be related to the upregulation of RyR3 expression and high levels of intracellular free calcium with increasing lead concentration in injured neurons.

Cognitive deficits and magnetic resonance spectroscopy in adult monozygotic twins with lead poisoning.

Seventy-one-year-old identical twin brothers with chronic lead poisoning were identified from an occupational medicine clinic roster. Both were retired painters, but one brother (J.G.) primarily removed paint and had a history of higher chronic lead exposure. Patella and tibia bone lead concentrations measured by K-X-ray fluorescence in each brother were 5-10 times those of the general population and about 2.5 times higher in J.G. than in his brother (E.G.). Magnetic resonance spectroscopy (MRS) studies examined N-acetylaspartate:creatine ratios, a marker of neuronal density. Ratios were lower in J.G. than in his brother. Scores on neurocognitive tests that assess working memory/executive function were below expectation in both twins. Short-term memory function was dramatically worse in J.G. than in his brother. These results demonstrate some of the more subtle long-term neurologic effects of chronic lead poisoning in adults. In particular, they suggest the presence of frontal lobe dysfunction in both twins, but more dramatic hippocampal dysfunction in the brother with higher lead exposure. The MRS findings are consistent with the hypothesis that chronic lead exposure caused neuronal loss, which may contribute to the impairment in cognitive function. Although a causal relation cannot be inferred, the brothers were genetically identical, with similar life experiences. Although these results are promising, further study is necessary to determine whether MRS findings correlate both with markers of lead exposure and tests of cognitive function. Nevertheless, the results point to the potential utility of MRS in determining mechanisms of neurotoxicity not only for lead but also for other neurotoxicants as well.

The protective role of astroglia in the early period of experimental lead toxicity in the rat.

Although the clinical manifestations of lead (Pb) neurotoxicity are documented, the subcellular mechanisms of its action are still an open question. The purpose of this study was to assess the function of nerve ending particles after acute lead exposure and to investigate whether it exerts a toxic effect on astroglial functions. The studies were performed using the rodent model of acute lead toxicity. Cellular fractions were used in biochemical measurements--synaptosomes and glial plasmalemmal vesicles (GPV). Since a procedure for the isolation of the fraction of astroglial origin has been developed, it becomes possible to investigate lead-astroglia interactions after in vivo exposure. It is of importance because most of the studies concerning lead toxicity were performed using astroglial culture systems. It was found that the uptake of glutamate (Glu) to the synaptosomes was lowered and KCl-dependent release was increased, suggesting the impairment of glutamatergic transmission leading to the elevation of extracellular amino acid concentration. In contrast, glutamate uptake to the GPV fraction was significantly elevated. The activity of the marker enzyme--glutamine synthetase (GS) was also significantly increased in the GPV fraction. The activation of glial functions suggest a regulatory role for these cells in the early period of acute lead toxicity.

Cumulative lead exposure in community-dwelling adults and fine motor function: comparing standard and novel tasks in the VA normative aging study.

BACKGROUND AND AIMS: Lead exposure in children and occupationally exposed adults has been associated with reduced visuomotor and fine motor function. However, associations in environmentally exposed adults remain relatively unexplored. To address this, we examined the association between cumulative lead exposure-as measured by lead in bone-and performance on the grooved pegboard (GP) manual dexterity task, as well as on handwriting tasks using a novel assessment approach, among men in the VA Normative Aging Study (NAS). METHODS: GP testing was done with 362 NAS participants, and handwriting assessment with 328, who also had tibia and patella lead measurements made with K-X-Ray Fluorescence (KXRF). GP scores were time (s) to complete the task with the dominant hand. The handwriting assessment approach assessed the production of signature and cursive lowercase l and m letter samples. Signature and lm task scores reflect consistency in repeated trials. We used linear regression to estimate associations and 95% confidence intervals (CI) with adjustment for age, smoking, education, income and computer experience. A backward elimination algorithm was used in the subset with both GP and handwriting assessment to identify variables predictive of each outcome. RESULTS: The mean (SD) participant age was 69.1 (7.2) years; mean patella and tibia concentrations were 25.0 (20.7)µg/g and 19.2 (14.6)µg/g, respectively. In multivariable-adjusted analyses, GP performance was associated with tibia (ß per 15µg/g bone=4.66, 95% CI: 1.73, 7.58, p=0.002) and patella (ß per 20µg/g=3.93, 95% CI: 1.11, 6.76, p=0.006). In multivariable adjusted models of handwriting production, only the lm-pattern task showed a significant association with tibia (ß per 15µg/g bone=1.27, 95% CI: 0.24, 2.29, p=0.015), such that lm pattern production was more stable with increasing lead exposure. GP and handwriting scores were differentially sensitive to education, smoking, computer experience, financial stability, income and alcohol consumption. CONCLUSIONS: Long-term cumulative environmental lead exposure was associated with deficits in GP performance, but not handwriting production. Higher lead appeared to be associated with greater consistency on the lm task. Lead sensitivity differences could suggest that lead affects neural processing speed rather than motor function per se, or could result from distinct brain areas involved in the execution of different motor tasks.