Neurotoxicity of polychlorinated biphenyls and related organohalogens

Abstract

Halogenated organic compounds are pervasive in natural and built environments. Despite restrictions on the production of many of these compounds in most parts of the world through the Stockholm Convention on Persistent Organic Pollutants (POPs), many "legacy" compounds, including polychlorinated biphenyls (PCBs), are routinely detected in human tissues where they continue to pose significant health risks to highly exposed and susceptible populations. A major concern is developmental neurotoxicity, although impacts on neurodegenerative outcomes have also been noted. Here, we review human studies of prenatal and adult exposures to PCBs and describe the state of knowledge regarding outcomes across domains related to cognition (e.g., IQ, language, memory, learning), attention, behavioral regulation and executive function, and social behavior, including traits related to attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). We also review current understanding of molecular mechanisms underpinning these associations, with a focus on dopaminergic neurotransmission, thyroid hormone disruption, calcium dyshomeostasis, and oxidative stress. Finally, we briefly consider contemporary sources of organohalogens that may pose human health risks via mechanisms of neurotoxicity common to those ascribed to PCBs.

Figure 1:

Exemplary non-coplanar and coplanar polychlorinated biphenyls (PCBs) of anthropogenic origin. Coplanar PCBs are also referred to as dioxin-like PCBs because of their ability to binding the AhR with high affinity, a mechanism considered to contribute to cancer risk, whereas non-coplanar PCBs with one or more ortho chlorine substitution have negligible AhR activity and have been shown to be neurotoxic through other mechanisms.

Figure 2.

Heuristic hypothesis modeling known mechanisms by which nondioxin-like (NDL) and dioxin-like (DL) persistent organic pollutants (POPs) influence mechanisms converging through their respective activities on ryanodine receptor (RyR) calcium channel complexes and expression of TDP-43. Expression of TDP-43 is significantly upregulated by a variety of dioxin-like environmental chemicals [4] and TDP-43 mediated neurotoxicity proceeds by Ca²⁺ dyshomeostasis and ER stress [37, 90] via mechanisms requiring RyR channel activity [2]. Such a model could serve as a basis for improving our understanding of adverse outcome pathways that contribute to risk for neurodevelopmental and neurodegenerative disorders, and the relationships between them. Abreviations: GAP, glycoprotein anchoring complex; IP₃R, inositol 1,4,5-trisphosphate receptor; nNOS, neuronal nitric oxide synthase; ROS, reactive oxygen species; RNS, reactive nitrogen species; SOCE, store-operated calcium channel; SERCA, sarcoplasmic/endoplasmic reticulum calcium ATPase; TDP-43, transactive response DNA binding protein 43; TRPC, canonical transient receptor protein; VDCC, voltage-dependent calcium channel.