Citation:

Kodavanti, P., J. Valdez, AND J. Yang. Chapter Seven: Neurochemical effects of Halogenated Organic Compounds: Possible adverse outcome pathways and structure-activity relationships. Edition 1, Chapter 7, Prasada Rao Kodavanti, Lucio G. Costa, Michael Aschner (ed.), Neurotoxicity of Halogenated Organic Compounds. ELSEVIER, AMSTERDAM, Holland, 10:279-324, (2023). https://doi.org/10.1016/bs.ant.2023.09.004

Impact/Purpose:

This Book Chapter is a part of a volume entitled "Neurotoxicity of Halogenated Organic Compounds" for series entitled "Advances in Neurotoxicology".  The current chapter focuses on (1) discussing the potential adverse outcome pathways (AOPs) in detail with data from both in vitro and in vivo studies (2). extend structure-activity relationship (SAR) among PCBs with other structurally related chemicals such as PBDEs and polychlorinated diphenyl ethers. Although several AOPs were postulated for PCB and other HOC-induced neurotoxic effects, changes in altered intracellular signaling processes including calcium and protein kinase C (PKC) signaling, neurotransmitters, oxidative stress, and thyroid hormone imbalance are predominant. We have discussed intracellular signaling pathway starting with neurochemical effects to genomic and proteomic changes to structural and functional changes both in vitro and in vivo studies.  Following this, SAR was conducted with different PCB congeners and extended the results to other structurally related HOCs.  The relevant use of AOPs to identify early biomarkers exposure and effect and understanding the SAR between different HOCs will improve our ability to assess both ecosystem health and human risk. For general public, other scientists working in this field, and regulators, this information is very useful to understand the health risks associated with this group of chemicals. 

Description:

Halogenated organic compounds (HOCs) are long-lived toxic compounds and are of major concern for ecosystem and health. The use and manufacture of several HOCs is banned or phased out in most countries, but some HOCs are still being used in several countries. The levels of certain HOCs, such as polychlorinated biphenyls (PCBs), declined in the environment, but new HOCs, such as polybrominated diphenyl ethers (PBDEs), have been increasing or stable. HOCs exposure is known to cause a wide spectrum of effects including reproductive, developmental, immunologic, carcinogenic, and neurotoxic effects. It is of particular concern that neurotoxic effects have been observed in humans at low parts per billion (ppb) environmental concentrations. Epidemiological and experimental evidence shows that PCB exposure is associated with motor, sensory, and cognitive deficits in humans and animal models. Although several adverse outcome pathways (AOPs) were postulated for PCB and other HOC-induced neurotoxic effects, changes in altered intracellular signaling processes including calcium and protein kinase C (PKC) signaling, altered neurotransmitters, oxidative stress, and thyroid hormone imbalance are predominant. The current chapter focuses on (1) discussing the potential AOPs in detail with data from both in vitro and in vivo studies (2) extend structure–activity relationship (SAR) among PCBs with other structurally related chemicals such as PBDEs and polychlorinated diphenyl ethers. For more details about role of thyroid hormone imbalance, please see Chapters 3 and 6. For the role of Ryanodine receptor in intracellular signaling processes, please see Chapter 4. This book chapter is a comprehensive review discussing molecular effects of HOCs at cellular level to the adverse effects seen in whole animals including structural, physiological, sensory, and functional changes.

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