Evidence Implicating Non-Dioxin-Like Congeners as the Key Mediators of Polychlorinated Biphenyl (PCB) Developmental Neurotoxicity

Abstract

Despite being banned from production for decades, polychlorinated biphenyls (PCBs) continue to pose a significant risk to human health. This is due to not only the continued release of legacy PCBs from PCB-containing equipment and materials manufactured prior to the ban on PCB production, but also the inadvertent production of PCBs as byproducts of contemporary pigment and dye production. Evidence from human and animal studies clearly identifies developmental neurotoxicity as a primary endpoint of concern associated with PCB exposures. However, the relative role(s) of specific PCB congeners in mediating the adverse effects of PCBs on the developing nervous system, and the mechanism(s) by which PCBs disrupt typical neurodevelopment remain outstanding questions. New questions are also emerging regarding the potential developmental neurotoxicity of lower chlorinated PCBs that were not present in the legacy commercial PCB mixtures, but constitute a significant proportion of contemporary human PCB exposures. Here, we review behavioral and mechanistic data obtained from experimental models as well as recent epidemiological studies that suggest the non-dioxin-like (NDL) PCBs are primarily responsible for the developmental neurotoxicity associated with PCBs. We also discuss emerging data demonstrating the potential for non-legacy, lower chlorinated PCBs to cause adverse neurodevelopmental outcomes. Molecular targets, the relevance of PCB interactions with these targets to neurodevelopmental disorders, and critical data gaps are addressed as well.

Polychlorinated Biphenyls (PCBs): Risk Factors for Autism Spectrum Disorder?

“…This exposure reduced nose-to-nose interactions between males, but enhanced sociability and social approach in females and males [82]. In contrast, the four rats studies (three of which were performed in the same laboratory), demonstrated that perinatal exposures to either a mixture of PCBs 47 and 77 [84] or Aroclor 1221 [83,85,86] generally decreased sociability metrics in males and had mixed effects in females depending on the dose and timing of administration [73]. These observations are consistent with the sex bias of ASD; however, it is not possible to determine from these studies whether the effects are attributable to a specific mechanistic or structural subgroup of PCBs.…”

“…While many of the earlier studies focused on the developmental neurotoxicity of legacy commercial mixtures, more recently, the neurodevelopmental impacts of individual PCB congeners or custom mixes based on PCB congener profiles documented in human tissues have been investigated. These studies are summarized in a recent review of animal studies published in the past decade that employed exposure paradigms relevant to humans, in terms of both the dose and exposure route [73]. The authors of the review concluded that the developmental neurotoxicity associated with exposures to legacy PCB mixtures is primarily mediated by NDL congeners.…”

“…Ultrasonic vocalizations (USVs) and sociosexual choice are also frequently used to assess sociability and communication in rodent models [80,81]. The animal literature describing the effects of developmental PCB exposure on social behavior was recently reviewed [69,73]. Briefly, five studies, one in mice [82] and four in rats [83][84][85][86], have been published that describe PCB effects on various metrics of sociability.…”

“…Mechanistic studies have shown that the dendrite-promoting activity of PCB 95 and 136 is mediated by the modulation of calcium signaling in neurons (reviewed in [45,63,73]). Early structure-activity relationship (SAR) studies revealed that NDL PCBs [126,127], but not DL PCBs [128], increase levels of intracellular Ca 2+ and modify calcium signaling in primary neuronal cell cultures.…”

Cellular and Molecular Mechanisms of Environmental Pollutants on Hematopoiesis

“…Nevertheless, PCBs continue to pose a significant risk to human health through exposure sources such as the continuous release from hazardous waste sites, PCB-contaminated equipment that is still in use, and contact with construction materials used in buildings erected prior to the PCB production ban. In addition, non-legacy PCB congeners have also been detected in paint and industrial pigments [ 186 ]. PCBs are still considered among the most important groups of food contaminants, and food and agricultural authorities strictly monitor the PCB contamination of foods.…”