Non-dioxin-like polychlorinated biphenyl neurotoxic equivalents found in environmental and human samples

Abstract

Non-dioxin like polychlorinated biphenyls (NDL PCB) are recognized neurotoxicants with implications on altered neurodevelopment and neurodegeneration in exposed organisms. NDL PCB neurotoxic relative potency schemes have been developed for a single mechanism, namely activity toward the ryanodine receptor (RyR), or combined mechanisms including, but not limited to, alterations of RyR and dopaminergic pathways. We compared the applicability of the two neurotoxic equivalency (NEQ) schemes and applied each scheme to PCB mixtures found in environmental and human serum samples. A multiple mechanistic NEQ predicts higher neurotoxic exposure concentrations as compared to a scheme based on the RyR alone. Predictions based on PCB ortho categorization, versus homologue categorization, lead to a higher prediction of neurotoxic exposure concentrations, especially for the mMOA. The application of the NEQ schemes to PCB concentration data suggests that PCBs found in fish from US lakes represent a considerable NEQ exposure to fish consuming individuals, that indoor air of schools contained high NEQ concentrations representing an exposure concern when inhaled by children, and that levels already detected in the serum of adults and children may contribute to neurotoxicity. With further validation and in vivo exposure data the NEQ scheme would help provide a more inclusive measure of risk presented by PCB mixtures.

Assessment of Polychlorinated Biphenyls and Their Hydroxylated Metabolites in Postmortem Human Brain Samples: Age and Brain Region Differences

“… a NEQ values for individual tissue extracts were calculated based on the NEFs established for the PCB homologue groups based on multiple mechanisms of action. 55 Data represent the median of the NEQ values of each homologue group across samples and the ΣNEQ from each sample. For analogous data based on NEFs established for the PCB homologue groups based on a single mechanism of action or NEFs established based on the number of ortho-chlorine substituents and a single or multiple mechanisms of action, see Table S10 .…”

“…We also calculated neurotoxic equivalent quotients (NEQs) by multiplying the tissue concentration with the published neurotoxic equivalency factors ( Table S10 ). 55 …”

Marine and Anthropogenic Bromopyrroles Alter Cellular Ca2+ Dynamics of Murine Cortical Neuronal Networks by Targeting the Ryanodine Receptor and Sarco/Endoplasmic Reticulum Ca2+-ATPase

“…4,41,42 The added risk contributed by current levels of RYR-active PCB congeners found in aquatic ecosystems was recently calculated and a multiple mechanistic neurotoxic equivalency scheme was proposed to better predict risk. 43 Evidence for the additivity of the PCBs, PBDEs, and related halogenated organics has been demonstrated. 44 Whether BrPyr interact with distinct or overlapping binding sites to these POPs remains to be determined.…”

“…Evidence for both of these mechanisms was previously provided in biochemical studies and is likely working in a feedforward manner to promote acute neurotoxicity . The neurodevelopmental ramifications of RYR-mediated disruption of neuronal network activity by POPs, including PCBs and PBDEs, and their potential contribution to neurodevelopmental deficits have been recently reviewed. ,, The added risk contributed by current levels of RYR-active PCB congeners found in aquatic ecosystems was recently calculated and a multiple mechanistic neurotoxic equivalency scheme was proposed to better predict risk . Evidence for the additivity of the PCBs, PBDEs, and related halogenated organics has been demonstrated .…”

Calcium Ions Aggravate Alzheimer’s Disease Through the Aberrant Activation of Neuronal Networks, Leading to Synaptic and Cognitive Deficits

“…More interestingly, the combined inhibition of both receptors paradoxically increases the amount of cytosolic Ca 2+ entering PC12 cells from the extracellular space, increasing cytotoxicity (Yang et al, 2019 ). In addition to InsP3R, RyR alone might be critical for modulating neurotoxicity in human microglia and THP-1 cells (Klegeris et al, 2007 ; Holland and Pessah, 2021 ). In cultured mammalian neurons, Xbpls ameliorates Aβ-induced neurotoxicity through an RyR-dependent mechanism (Fernandez-Funez et al, 2010 ).…”