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

• Published in: Environmental science & technology Vol. 53; no. 7; pp. 3948 - 3958
• Main Authors: Sethi, Sunjay, Morgan, Rhianna K, Feng, Wei, Lin, Yanping, Li, Xueshu, Luna, Corey, Koch, Madison, Bansal, Ruby, Duffel, Michael W, Puschner, Birgit, Zoeller, R. Thomas, Lehmler, Hans-Joachim, Pessah, Isaac N, Lein, Pamela J
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 02.04.2019
• Subjects: Brain; Child; Congeners; Enviromental Science; Environmental Pollutants; Female; Gas chromatography; Humans; Mass spectrometry; Mass spectroscopy; Metabolites; Microsomes; Miljövetenskap; Mimicry; Neurodevelopmental disorders; Neurotoxicity; PCB; PCB compounds; Pollutants; Polychlorinated Biphenyls; Pregnancy; Receptors, Thyroid Hormone; Risk assessment; Ryanodine Receptor Calcium Release Channel; Ryanodine receptors; Serum; Sulfates; Thyroid; Thyroid gland
• ISSN: 0013-936X; 1520-5851; 1520-5851
• DOI: 10.1021/acs.est.9b00535

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 [3H]­ryanodine to RyR1-enriched 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.