Toxins

Toxic Agents

Environmental factors have long been associated with a wide range of neurodevelopmental deficits. At high levels of prenatal exposure environmental toxins are capable of producing cognitive, motor, behavioural and sensory disturbances, whereas the effects of lower levels of exposure on the fetus are suposedly more subtle and dependent on the timing and dose of the chemical agent. For example perinatal and childhood exposure to high doses of heavy metals lead and mercury can result in encephalopathy, convulsions or celebral palsy. The effects of lower-dose exposures are less clear, although behavioural alterations and impairments in intellectual function and attention, as well as increased seizure suceptibility have been suggested [16136561, 12224761, 15970329, 2294437]. Recent animal research points to influence of perinatal exposure to various toxins on neuronal development and functioning. It has been proposed that exposure to PCBs as well as various other synthetic chemicals may contribute to common developmental disorders [12060832, 12060832, 17268844].

Ion channels are a target of a many environmental toxins that are capable of altering their activity. Numerous environmental agents, including low frequency electromagnetic fields, affect functioning of membrane as well as intracellular calcium channels, thus affecting cellular calcium homeostasis, in many types of cells, including neurons. These effects are widely believed to the main mechanism behind their neurotoxicity [15000519, 8247389].

Of special interest might be the findings of a series of murine studies pointing to links between viral infections and absorbtion and tissue/organ distribution of environmental toxins, in the light of reports indicating impaired detoxification and accumulation in the body of environmental toxins in ASD individuals (see Infectious _Agents).

Lead

While lead competes with calcium at the plasma membrane for entry into the cell, it also interferes with intracellular calcium buffering systems and its regulatory actions in various cell functions [8247414, 7504228]. Through these actions lead is believed to be able to disrupt the blood-brain barrier, both by damaging the astrocytes and the endothelial cells [1671748, 9622620] (see BBB). Developing nervous system is thought to be particularly sensitive to these effects, as lead is capable of rapidly crossing the blood brain barrier and affecting neuronal function, and long-term effects of lead poisoning are believed to result in various cognitive, behavioural and motor impairments [16501435, 12835126, 11106867].

While several types of ion channels are affected by lead, L-type calcium channels appear particularly sensitive. It is of interest to note that, while the main action of lead is the blockade of these channels and inhibition of calcium traffic, several in vitro studies have also noticed some unexpected effects, like the enhancement of calcium flow in some cells or the sudden unblock of channels following strong depolarisation [1660583, 9223552].

Iron

Although iron is an essential mineral for normal cellular physiology, its excessive levels can result in damage to the cell. Impaired calcium homeostasis and oxidative stress with excessive production of ROS (see Oxidative Stress) is believed to be one of the consequences of both acute and chronic body iron overload.

Various calcium channel antagonist have been observed in vitro and in animal studies to attenuate the neurotoxic effects of iron by inhibiting excessive entry of both iron and calcium ions, implicating effects of iron on membrane permeability and permissivness of calcium channels [16528447, 12184662, 12937413]. In addition to overactivation of voltage gated channels, iron toxicity also appears to be closely related to excessive activation of NMDA glutamate receptors [16908409].

Mercury

Both organic and inorganic mercurials are neurotoxic. The neurotoxic effects of both acute poisoning and long-term environmental exposure to mercury toxins are attributed in great part to their interaction with calcium channels and modulation of levels of calcium in the cell [12062935, 16326920, 16465247, 7641225].

Activation of M3 muscarinic receptors was found to contribute to elevations in intracellular calcium and by methylmercury. Prior down-regulation of muscarinic and IP3 receptors with Bethanecol protected against neuronal cell death, indicating interaction of mercury with muscarinic and IP3 receptors to cause calcium release from the intracellular pools [15141107]. Of note in this context are the reported benefits of Bethanecol treatment in a subgroup of individuals with autism [10867750].

Migration of neuronal and nonneuronal cells during development was observed in vitro to be strongly influenced by calcium oscilation and sensitive to dose-dependent thimerosal-induced releases from intercellular stores [16720042]. This increase of responsiveness of IP3-receptors by thimerosal, an organic mercury compound, appears to be able to modulate sensitivity to calcium of parathyroid cells [10598273].

In addition to effects of mercury on neuronal cells, of equal interest are the findings of its negative effects in immune responses. Dysturbances of calcium homeostasis induced by low-level chronic exposure to mercury is suggested to be one of the mechanisms behind immune dysfunction and tendency towards development of chronic disease following viral infection [9653674, 8952707]. Both organic and inorganic mercury have been observed to screw immune responses and induce autoimmunity in mice, with mouse strains that are genetically suceptible to autoimmunity showing most pronuonced developmental disturbances following exposure to ethylmercury [17084957, 15184908] (see also Viruses/Bacteria). Dendritic cells, crucial for the first-line response of the immune system towards external pathogens, have recently demonstrated particular sensitivity to changes in calcium levels as induced by ethylmercury-containing perservative thimerosal [16835063] (see Immunity/Inflammation).

The tendency of increased persistence of virus with methylmercury exposure may turn out to be of particular relevance in autism, as this toxin has been observed in a murine model to change viral myocarditis in a direction compatible with the development of chronic inflammatory disease. Amongst other markers significantly raised levels of calcium and decreased levels of zinc were recorded in the inflamed heart [11314973, 8682094].

The continuous application of heavy metals lead and mercury in vivo resulted in their accumulation in brain cells and the occurrence of delayed toxic effects in rat fetuses. It was shown that when methylmercury is applied at non-toxic concentrations it becomes neurotoxic under pro-oxidative conditions. Lead and mercury induce glial cell reactivity, a hallmark of brain inflammation and increase the expression of the amyloid precursor protein. Mercury also stimulates the formation of insoluble beta-amyloid, which plays a crucial role in the pathogenesis of AD and causes oxidative stress and neurotoxicity in vitro. Based on their results and reviews of previous findings authors suggest that those heavy metals may contribute to the etiology of neurodegenerative diseases [16898674] (see Related Disorders)

Other toxic agents

Various other environmental toxins are capable of modulating the functioning of calcium channels, including various organophosphates, phthalates and other industrial compounds used as pesticides, solvents, flame retardants, plasticisers etc [11750043, 16300829, 16686424, 16325978, 10869474]. Nerve agent Sarin and structuraly similar organophosphates have demonstrated ability to induce changes in neuronal gene expression, with calcium channel proteins being some of the most affected ones [16376859]. Of particular interest are the observations of hightened vulnerability to some of these agents due to inborn weakness in detoxification pathways in some individuals and their association with autism [16027737, 17084875].

Carbon monoxide [11743890], sulfur dioxide [16857312], cadmium [15954739], nicotine [15764844], ethanol [16555300], low frequency electromagnetic fields [17941084, 15036948 15110298], ultrasound [2685832] and X-rays [9096258] are amonst some of the other factors capable of modulating membrane permeability and cellular calcium metabolism.

In vitro and animal studies have demonstrated that various calcium antagonists, in particular nimodipine and other dihydropyridines, are able to attenuate negative effects of these agents on cellular function and survival [17941084, 16635102, 2156356].

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