Neurotoxicity lead effects

Mantere P, Haenninen H, Hemberg S. 1982. Subclinical neurotoxic lead effects Two-year follow-up studies with psychological test methods. Neurobehav Toxicol Teratol 4 725-727. 

Impairment of heme-biosynthesis as well as neurotoxic lead effects, especially effects on the central nervous system (C.N.S.)/ are considered to be early signs of incipient damage due to lead. Neurobehav-ioral studies in animals show that, for example, deficit of learning-performance already occurs at blood-lead concentrations between 20 and 30 yg/dl in rats, if the exposure is not only postnatal, but pre- and neonatal as well, i.e. when it takes place during the period of brain maturation, also (Winneke et al., 1977 1982a). 

Prolonged periods of exposure to natural, synthetic, or man-made chemical substances cause neurotoxicity. The effects of neurotoxicity result in a variety of health disturbances. In simple terms, neurotoxic chemical substances change the normal activity of the nervous system, eventually leading to disruption of the network of neurons. Thus, the key cells of neural transmission and signal processing in the brain and other parts of the nervous system get damaged. 

Laurenza I, Pallocca G, Mennecozzi M, Scelfo B, Pamies D, Bal-Price A (2013) A human pluripotent carcinoma stem cell-based model for in vitro developmental neurotoxicity testing effects of methylmercury, lead and aluminum evaluated by gene expression studies. Int J Dev Neurosci 31(7) 679-691... 

Two enzyme systems have shown themselves to be extremely sensitive to lead at low levels. The first of these is D-amino laevulinic acid dehydratase (d-ALAD), the initial and rate limiting step in the porphyrin synthetic pathway. In both experimental (Barlow et al., 1977) and clinical studies (Piomelli et al., 1980) this enzyme is potently inhibited by lead. In a review of dose-dependent low level lead effects, Zielhuis (1975) calculated a no effect level for this enzyme at about 10/tg Pb/lOOml blood in man. Other enzymes in the porphyrin synthetic pathway are also affected by lead, e.g. ferrochelatase, the enzyme responsible for the insertion of haem into the porphyrin precursor protoporphyrin IX (Moore, 1975), but this is probably due to D-ALAD-related interactions. Silbergeld and Lamon (1980) have speculated that the neurotoxic effects of lead may be due in part to a competitive interaction involving amino laevulinic acid at neuronal receptors, as there may be similarities between features of lead toxicity and some of the porphyrinopathic diseases (Moore et al., 1980). 

In conclusion, data from low level studies, in which vascular change and undernutrition do not occur, suggest the possibility of specific lead effects on neuronal populations in the forebrain (notably the hippocampus) and cerebellum. To what extent such effects are related to the suspected human problem of subclinical lead neurotoxicity may only emerge after prolonged and intensive study. 

Taxanes (paclitaxel, docetaxel) are derivatives of yew tree bark (Taxus brevifolia). They stabilize microtubules in the polymerized state leading to nonfunctional microtubular bundles in the cell. Inhibition occurs during G2- and M-phases. Taxanes are also radiosensitizers. Unwanted effects include bone marrow suppression and cumulative neurotoxicity. 

Starvation or disease can lead to rapid release of the stored xenobiotic and to delayed toxic effects. In one well-documented case in the Netherlands (see Chapter 5), wild female eider ducks (Somateria mollissima) experienced delayed neurotoxicity caused by dieldrin. The ducks had laid down large reserves of depot fat before breeding, and these reserves were run down during the course of egg laying. Dieldrin concentrations quickly rose to lethal levels in the brain. Male eider ducks did not lay down and mobilize body fat in this way and did not show delayed neurotoxicity due to dieldrin. 

Broadly speaking, the direct behavioral effects of neurotoxic pollutants on wild animals may be on feeding, breeding, or avoidance of predation (Beitinger 1990), or any combination of these. Any of these changes may have adverse effects on populations. Additionally, in the natural world, populations may be affected indirectly because of neurotoxic and behavioral effects on other species. Thus, a population decline of one species due to a behavioral effect of a pollutant may lead to a consequent decline of its parasites or predators, even though they are not themselves directly affected by the chemical. Direct effects will now be discussed before considering indirect ones. 

Turning now to indirect effects of neurotoxic pollutants, the status of predators and parasites can be affected by reductions in numbers of the species that they feed upon. Thus, the reduction in numbers of a prey species due to a behavioral effect can, if severe enough, cause a reduction in numbers of a predator. Also, as mentioned earlier, behavioral effects upon a prey species may lead to selective bioaccumulation of persistent neurotoxic pollutants such as DDT and dieldrin by predators thus, a behavioral effect may be hazardous for predator and prey alike ... 

Interest in the PGs has recently reverted to their precursor arachidonic acid (AA), which seems to be able to act intracellulary as a second messenger, and also extra-cellularly. In this latter mode it may play a part in LTP. It is known that AA produces a long-lasting enhancement of synaptic transmission in the hippocampus that resembles LTP and in fact activation of NMDA receptors leads to the release of AA by phospholipase A2 (see Dumuis et al. 1988) and inhibition of this enzyme prevents the induction of LTP. AA has also been shown to block the uptake of glutamate (see Williams and Bliss 1989) which would potentiate its effects on NMDA receptors. This would not only prolong LTP but also cause neurotoxicity. 

Low concentrations of solubilised jS-albumin inhibit ACh release in slices from rat hippocampus and cortex areas which show degeneration in AzD, but not in slices from the striatum which is unaffected. While not totally specific to ACh, since some inhibition of NA and DA and potentiation of glutamate release have been reported, this effect is achieved at concentrations of A/i below those generally neurotoxic. Since jS-amyloid can inhibit choline uptake it is also possible (see Auld, Kar and Quiron 1998) that in order to obtain sufficient choline for ACh synthesis and the continued function of cholinergic neurons, a breakdown of membrane phosphatidyl choline is required leading to cell death (so-called autocannibalism), /i-amyloid can also reduce the secondary effects of Mi receptor activation such as GTPase activity... 

MPTP, into dopamine neurons seems to be essential, and blockade of that aeeumulation prevents the neurotoxieity. MPP+ also ean be transported into norepinephrine neurons (Javitch et al. 1985), leading to neurotoxicity toward cortical norepinephrine neurons, an effect blocked by inhibitors of the norepinephrine uptake carrier (Sundstrom and Jonsson 1985). 

In leukemia, the intensified use of methotrexate and glucocorticoids is responsible for causing an increased frequency of neurotoxicity and, in older children and adults, avascular necrosis of bone. High cumulative doses of anthracyclines can cause cardiomyopathy. Cranial irradiation causes neuropsychologic deficits and endocrine abnormalities that lead to obesity, short stature, precocious puberty, and osteoporosis.3 As newer and more intensive treatments enter clinical trials, close observation for long-term side effects will assume even greater importance.24... 

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