Comparative Analyses of the 12 Most Abundant PCB Congeners Detected in Human Maternal Serum for Activity at the Thyroid Hormone Receptor and Ryanodine Receptor

Abstract

Polychlorinated biphenyls (PCBs) pose significant risk to the developing human brain; however, mechanisms of PCB developmental neurotoxicity (DNT) remain controversial. Two widely posited mechanisms are tested here using PCBs identified in pregnant women in the MARBLES cohort who are at increased risk for having a child with a neurodevelopmental disorder (NDD). As determined by gas chromatography-triple quadruple mass spectrometry, the mean PCB level in maternal serum was 2.22 ng/mL. The 12 most abundant PCBs were tested singly and as a mixture mimicking the congener profile in maternal serum for activity at the thyroid hormone receptor (THR) and ryanodine receptor (RyR). Neither the mixture nor the individual congeners (2 fM to 2 μM) exhibited agonistic or antagonistic activity in a THR reporter cell line. However, as determined by equilibrium binding of [ 3 H]ryanodine to RyR1enriched microsomes, the mixture and the individual congeners (50 nM to 50 μM) increased RyR activity by 2.4−19.2-fold. 4-Hydroxy (OH) and 4-sulfate metabolites of PCBs 11 and 52 had no TH activity; but 4-OH PCB 52 had higher potency than the parent congener toward RyR. These data support evidence implicating RyRs as targets in environmentally triggered NDDs and suggest that PCB effects on the THR are not a predominant mechanism driving PCB DNT. These findings provide scientific rationale regarding a point of departure for quantitative risk assessment of PCB DNT, and identify in vitro assays for screening other environmental pollutants for DNT potential.

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

“…A range of PCB doses and routes of administration have been employed in animal studies, and, in most cases, PCB levels were not measured in exposed animals. To provide a point of reference for this section, the PCB body burden in contemporary humans is reported to be about 2.2 ng/mL in maternal sera [69] and between 0.7 to 66 ng/g wet weight in postmortem brain tissue from individuals across the U.S. and Europe [56,[70][71][72]. PCB levels in the brain tissue of juvenile rats exposed to Aroclor 1254 at 1 mg/kg/day throughout gestation and lactation via the maternal diet ranged from 0.5 to 3.0 ng/g wet weight [47].…”

“…However, the data regarding the activity of PCBs and their metabolites at the THR or on THR-mediated gene transcription are inconsistent, with studies variably reporting agonistic effects, antagonistic interactions, or no activity [150,151,201,202]. A recent study that evaluated the THR activity of an NDL PCB mixture that proportionally mimics the PCB congener profile detected in the blood of pregnant women in Northern California observed neither agonistic nor antagonistic activity of these congeners when tested singly or in combination across a broad range of concentrations [69].…”

“…Over the past decade, PCB congeners not found in the mixtures synthesized prior to the ban on commercial PCB production are increasingly being identified in the human chemosphere [6,69,256]. Most of these are LC-PCBs (reviewed in [8]).…”

“…The non-legacy LC-PCB, PCB 11, has recently been detected in the serum of dairy animals [257] and in commercial cow's milk in Northern California [258]. Of even greater concern, PCB 11 has also been found in serum of pregnant women living in Northern California [13,69] as well as women and their adolescent children living in the greater Chicago area and rural Iowa [6]. Analysis of PCBs in the serum of pregnant women at increased risk for having a child with an NDD revealed that the non-legacy LC-PCBs 28 and 11 were the two most abundant PCB congeners, and together they comprised almost 75% of the PCB burden in the maternal serum samples [69].…”

Developmental exposure to polychlorinated biphenyls (PCBs) in the maternal diet causes host-microbe defects in weanling offspring mice

“…Yet whether this dysbiosis is caused by genetic or environmental stimuli, or both, remains unknown. Using a mixture of PCBs based on the congener profile found in pregnant women at increased risk of having a child with a NDD (Barkoski et al, 2018;Sethi et al, 2019), we asked whether developmental exposure to PCBs impacts colonization of the gut microbiota, intestinal permeability, and the mucosal immune response. Finally, we hypothesized that mice that express heritable mutations that contribute to abnormal neuronal Ca 2þ dynamics and are associated with neurobehavioral impairments would be more susceptible to PCB-induced gut effects than WT congenic mice.…”