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Neurotoxicity of persistent organic pollutants: possible mode(s) of action and further considerations - PubMed

  • ️Sun Jan 01 2006

Neurotoxicity of persistent organic pollutants: possible mode(s) of action and further considerations

Prasada Rao S Kodavanti. Dose Response. 2006.

Abstract

Persistent organic pollutants (POPs) are long-lived toxic organic compounds and are of major concern for human and ecosystem health. Although the use of most POPs is banned in most countries, some organochlorine pesticides are still being used in several parts of the world. Although environmental levels of some POPs such as polychlorinated biphenyls (PCBs) have declined, newly emerging POPs such as polybrominated diphenyl ethers (PBDEs) have been increasing considerably. Exposure to POPs has been associated with a wide spectrum of effects including reproductive, developmental, immunologic, carcinogenic, and neurotoxic effects. It is of particular concern that neurotoxic effects of some POPs have been observed in humans at low environmental concentrations. This review focuses on PCBs as a representative chemical class of POPs and discusses the possible mode(s) of action for the neurotoxic effects with emphasis on comparing dose-response and structure-activity relationships (SAR) with other structurally related chemicals. There is sufficient epidemiological and experimental evidence showing that PCB exposure is associated with motor and cognitive deficits in humans and animal models. Although several potential mode(s) of actions were postulated for PCB-induced neurotoxic effects, changes in neurotransmitter systems, altered intracellular signalling processes, and thyroid hormone imbalance are predominant ones. These three potential mechanisms are discussed in detail in vitro and in vivo. In addition, SAR was conducted on other structurally similar chemicals to see if they have a common mode(s) of action. Relative potency factors for several of these POPs were calculated based on their effects on intracellular signalling processes. This is a comprehensive review comparing molecular effects at the cellular level to the neurotoxic effects seen in the whole animal for environmentally relevant POPs.

Keywords: Neurotoxicity; intracellular signaling; mode of action; neurotransmitters; persistent organic pollutants; polybrominated diphenyl ethers; polychlorinated biphenyls; structure-activity relationships; thyroid hormones.

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Figures

FIGURE 1
FIGURE 1

Structural similarities between polyhalogenated aromatic hydrocarbons and thyroxine (T4). The numbers on the structures indicate the possible position for halogens. o = ortho; m = meta; p = para; PCB = polychlorinated biphenyl; T4 = Thyroxine; PBDE = polybrominated diphenyl ether; PCDE = polychlorinated dipheyl ether; DDT = 1,1,1-trichloro-2,2-bis[p-chlorophenyl]-ethane.

FIGURE 2
FIGURE 2

Disruption of thyroid hormone homeostais by polychlorinated biphenyls and the possible mechanisms. The solid arrow in blue shows the normal process for TH production and clearance. The solid arrow in red shows the predominant pathway for the effects of PCBs on TH homeostasis. The binding of PCBs to transport proteins in blood not only results in the reduction of circulating TH levels, but also gets transported to the organs to elicit an adverse effect. TRH, Thyrotropin-releasing hormone; TSH, Thyroid-stimulating hormone; TBG, Thyroxine-binding globulin; TTR, Transthyretin; T4, Thyroxine; UDPGT, UDP-glucuronyltransferase.

FIGURE 3
FIGURE 3

Possible mechanism(s) for developmental neurotoxicity of persistent organic pollutants (e.g., PCBs). The polyhalogenated aromatic hydrocarbons (PAHs) can be separated as non-coplanar and coplanar compounds. Non-coplanar parent compounds and hydroxy metabolites affected intracellular signalling, thyroid hormone (TH) homeostasis, and neurotransmitters. On the other hand, coplanar parent compounds have effects only on TH while no effects on neurotransmitters and intracellular signaling. The coplanar metabolites have been shown to affect intracellular signaling and TH. In the case of non-coplanar PAHs, all three proposed mechanisms might be working together to cause neurotoxic response while coplanar PAHs could be working through one or two of the proposed mechanisms to cause neurotoxic response. The changes in these proposed pathways could lead to changes in the gene expression of several transcription factors that may lead to altered neuronal plasticity and development, and finally lead to a neurotoxic response such as motor dysfunction or learning and memory deficits.

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