Elsevier

Toxicology Letters

Volumes 102–103, 28 December 1998, Pages 631-635
Toxicology Letters

Neurotoxicity of environmental chemicals and their mechanism of action

https://doi.org/10.1016/S0378-4274(98)00271-9Get rights and content

Abstract

Despite a ban on their manufacture in 1977, polychlorinated biphenyls (PCBs) are still found in significant quantities in the environment. Developmental exposure to PCBs and related compounds has been reported to be neurotoxic in human and animals. Research in our laboratory has focused on the possible site(s) and mechanism(s) of PCB-induced developmental neurotoxicity. Recent experiments with rats found that developmental exposure to Aroclor-1254 (ARC) affects the acquisition of a lever press response and produces long-term changes in calcium buffering and protein kinase C (PKC) activity in the brain. In vitro studies in our laboratory have found that ARC increases [3H]phorbol ester binding, an indirect measure of PKC translocation, and inhibits calcium buffering in microsomes and mitochondria. Other experiments indicate that PCB congeners with chlorine substitutions at ortho- or low lateral substitutions are active in vitro, while non-ortho-substituted congeners are less active or inactive. Other research suggests that the lack of coplanarity of the PCB molecule is related to in vitro activity of PCB congeners.These studies indicate that in vivo developmental exposure to PCBs alters behavior and second messenger systems during adulthood, while in vitro experiments indicate that nervous system activity is related to ortho-substituted congeners that tend to be non-coplanar in configuration. Our results are consistent with the hypothesis that developmental neurotoxicity of ARC is due, in part, to the presence of ortho-substituted PCB congeners.

Introduction

Human research indicates that developmental exposure to mixtures of polychlorinated biphenyls (PCBs) and related compounds can affect nervous system development and impair cognitive function (Harada, 1976; Hsu et al., 1985; Jacobson et al., 1985; Rogan et al., 1988; Jacobson et al., 1990; Rogan and Gladen, 1992; Sauer et al., 1994; Huisman et al., 1995). Research conducted in a variety of animal species supports the conclusion that developmental exposure to PCBs can have long-term effects on behavioral and neurological functioning (Tilson et al., 1990; Seegal and Shain, 1992; Schantz et al., 1995).

A number of laboratories have focused on the possible cellular changes underlying functional alterations produced by developmental exposure to PCBs. For example, it has been reported that perinatal exposure to 3,4,3′,4′-tetrachlorobiphenyl altered the behavioral development in mice and decreased brain dopamine concentrations and receptor binding (Tilson et al., 1979; Agrawal et al., 1981). It has also been reported that post-natal exposure to 3,4,3′,4′-tetrachlorobiphenyl produced age-dependent changes in brain cholinergic muscarinic receptors of mice (Eriksson, 1988Eriksson et al., 1991). Chou et al. (1979)reported that mice exposed to 3,4,3′,4′-tetrachlorobiphenyl during development exhibited abnormal neurological development associated with cylindrical peninsulas in the spinal cord and cranial nerve roots. These studies indicate that developmental exposure to this congener can have long-term effects on behavior and brain neurochemistry.

Other research has focused on the developmental effects of PCB mixtures. For example, Seegal (1994)reported that developmental exposure to Aroclor 1016 increased brain dopamine concentrations, without affecting other neurotransmitters, such as norepinephrine or serotonin. Morse (1995), on the other hand, found that developmental exposure to Aroclor 1254, a PCB mixture with a higher chlorine content than Aroclor 1016, had persistent effects on brain serotonin turnover without affecting dopaminergic systems. Developmental exposure to Aroclor 1254 has also been reported by Juarez de Ku et al. (1994)to decrease hippocampal and basal forebrain choline acetyltransferase activity in the offspring.

Research in our laboratory has focused on characterization of the developmental effects of Aroclor 1254. Goldey et al. (1995), for example, found that developmental exposure of rats to Aroclor 1254 caused permanent auditory deficits amounting to a 20–30 dB threshold shift at relatively low (1 kHz) frequencies. These effects appear to be related to PCB-induced hypothyroidism during development. Other experiments found that Aroclor 1254 affected the rate of acquisition of an autoshaped operant response for food reinforcement and performance of a reference memory task in the Morris water maze (Mundy et al., 1998). Seo et al. (1998)reported that although maternal exposure to Aroclor 1254 had no effect on the acquisition of a food-reinforced spatial memory task, long-term potentiation in the hippocampus of the offspring was affected. These results suggest that the effects of Aroclor 1254 on cognitive function and performance may be task- or measure-dependent.

Work from our laboratory (Kodavanti and Tilson, 1997) has also examined the effects of PCBs on calcium homeostasis and signal transduction mechanisms. When calcium enters the cell, it is sequestered by a number of organelles, such as mitochondria and microsomes or extruded from the cell by enzymes, such as Ca2+-ATPase in the plasma membrane and the Na+/Ca2+ exchanger (Carafoli, 1987). These homeostatic processes operate to maintain intracellular levels of calcium within a range of 0.1–0.3 μM. Increasing levels of cytosolic free calcium could increase a number of calcium-dependent processes, such as the translocation of protein kinase C from the cytosol to the membrane (Nishizuka, 1992). Perturbations in Ca2+ homeostasis have been shown to affect neuronal growth (Kater and Mills, 1991) and sustained increases in intracellular calcium have been associated with cell injury (Choi, 1985). Studies measuring the incorporation of [32P] into neurogranin from γ-[32P]ATP found a decreased protein kinase C (PKC) activity in the frontal cortex of rats exposed developmentally to Aroclor 1254, suggesting a downregulation of this enzyme. Other measurements indicated that the uptake of [45Ca2+] by microsomes was decreased in brains of Aroclor-1254-exposed animals, suggesting that homeostatic calcium sequestration mechanisms were impaired. As a number of developmental processes are calcium-dependent, it is possible that Aroclor-1254-induced functional changes are related to alterations in calcium homeostasis.

Section snippets

Effects of pcbs in vitro

The in vivo neurochemical results showing altered calcium homeostasis and PKC activity following developmental exposure to Aroclor 1254 have also been observed in vitro by our laboratory. Granule cells from post-natal rat cerebellum were cultured and exposed to various PCB mixtures. Effects on the activation of PKC by the PCBs were estimated by measuring [3H]phorbol ester binding, which has high affinity for the activated form of PKC (Worley et al., 1986; Vaccarino et al., 1991). Increases in

Structure activity relationships (sar)

Mixtures of PCBs, such as Aroclor 1254 are comprised of 60 or more congeners combined to yield a product containing a certain percentage of chlorinated compounds. PCB mixtures were used for a variety of industrial purposes based on their degree of chlorination. Research from several laboratories has found that many of the toxic effects associated with PCB exposure including thymic atrophy, immunotoxicity, endocrine and reproductive toxicity, and carcinogenicity are associated with a high

Conclusions

PCBs are members of a class of halogenated hydrocarbon compounds that were banned from manufacture in the United States in 1977. Due to their environmental persistence, PCBs are still found in biological samples of wildlife and ecosystems. Developmental neurotoxicity has been reported in children exposed to PCBs and confirmed in various laboratory animal models. Studies in our laboratory to understand the cellular basis for PCB-induced neurotoxicity have found that maternal exposure to Aroclor

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