The neurochemical effects of lead

Although it is possible to measure certain neurochemical parameters in humans, the understanding of molecular mechanisms of lead toxicity must depend on animal experimentation. Alterations in neurochemistry may precede other neurotoxic effects and be the basis for the expressions of altered behaviour, pharmacological response or cell pathology. 

Before reviewing the reported effects of lead on neurochemistry, it is necessary to discuss the more general effects of lead on brain biochemistry. A great deal of work has been carried out on the possible general metabolic effects of lead, but for the purposes of this chapter, only biochemical effects on the brain will be discussed. 

The first general biochemical study of the effects of lead on cerebral cortex and cerebellum, using 4% lead carbonate in the maternal diet from birth, was made by Michaelson (1973). He found a transient postnatal growth retardation and reduction of cerebral and cerebellar wet weights. The cerebellum showed increased water and reduced DNA content, suggesting a 15-20% deficit in cell numbers. DNA in the cerebrum and RNA and protein in both areas differed only marginally from controls, although all were consistently 

Phenylalanine uptake Glycine Forebrain 40-90 days No change Silbergeld and Goldberg, 1975 

Glucose-6-phosphate dehydrogenase day 20 Decreased at high dose Gelman et al, 1979 

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Other neurochemical studies have not been carried out in lead-exposed humans. It is difficult to measure neurochemical functions in vivo without recourse to such techniques as cerebrospinal fluid collection. However, the reported effects of lead exposure in rodents on plasma concentrations of prolactin (Govoni et al., 1978) and other pituitary hormones (Petrusz et al., 1979), and tetrahydrobiopterin (Leeming and Blair, 1980 McIntosh et al., 1982) would suggest that similar studies in humans might be considered. 

The reported neurochemical effects of lead are, as has been seen, enormous. They can be broadly summarized by neurotransmitter system cholinergic impairment at relatively high levels (usually in the presence of non-specific effects), dopaminergic effects at low levels, and impairment at higher levels (in the presence of obvious non-specific effects), GABAergic effects at levels where a complication from the interaction with D-amino laevulinic acid also occurs. There is also a mixed bag of effects on enkephalin, adenyl cyclase, 5-hydroxytrypamine and other putative aminergic neurotransmitters. 

In the last 10 years, the neurotoxicological effects of lead have received intense attention, and some of the conclusions reached have been discussed here. Effects of lead have been seen at the behavioural, neurochemical and structural levels in the brain. As it appears that atmospheric lead dispersal will now begin to fall, the emphasis of research into the effects of lead is likely to change again. 

Given the difficulties in formulating a comparative basis for internal exposure levels among different species, the primary value of many animal studies, particularly in vitro studies, may be in the information they can provide on basic mechanisms involved in lead neurotoxicity. A number of key in vitro studies are summarized in US EPA (1986a). These studies show that significant, potentially deleterious, effects on nervous system function occur at in situ lead concentrations of 5 /xmol/L and possibly lower. This suggests that, at least on an intracellular or molecular level, there may exist essentially no threshold for certain neurochemical effects of lead. The relationship between PbB levels and lead concentrations at extra- or intracellular sites of action, however, remains to be determined. 

As in AD, knowdedge of the neurotransmitter deficiency underlying PD, in this case dopamine, has been the basis for the development of therapy. Early studies show ed that cerebral dopamine was concentrated in the shiatum and that levodopa, the precursor to dopamine, could reverse the akinetic effects of the dopamine-depleting agent reserpine in experimental animals (Carlsson et al., 1957, 1958). Eventually, the identification of shiatal dopamine depletion as a key neurochemical finding in parkinsonian brains lead to heatment wdth levodopa in humans and to the subsequent advent of compounds that mimic the effects of dopamine or prolong its action (Table 39.2). 

Psychotic reactions triggered by LSD have been reported to be aborted by neuroleptics, beta blockers and pargyline type molecules. These drugs block the neurochemical sequence of events that allow the drug to be active. More study on molecules which block or abort LSD effects should be researched further as it will lead to a better understanding of neurochemical mechanisms. 

The binding of PCP to its receptor initiates a series of coupled neurochemical events eventually leading to the expression of behavior. One such coupling reaction was described by BLAUSTEIN as a blockade of transmembrane channels that transport K+ into the neuronal cells. Since K+ movements are part of the process of neurotransmission between neurons, this effect of PCP may explain the results of studies by MARWAH and by JOHNSON, in which several neurotransmitter systems were shown to be involved in the actions... 

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