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

Sunjay Sethi; Rhianna K Morgan; Wei Feng; Yanping Lin; Xueshu Li; Corey Luna; Madison Koch; Ruby Bansal; Michael W Duffel; Birgit Puschner; R Thomas Zoeller; Hans-Joachim Lehmler; Isaac N Pessah; Pamela J Lein

doi:10.1021/acs.est.9b00535

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

Journal article

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

Sunjay Sethi, Rhianna K Morgan, Wei Feng, Yanping Lin, Xueshu Li, Corey Luna, Madison Koch, Ruby Bansal, Michael W Duffel, Birgit Puschner, …

Environmental science & technology, Vol.53(7), pp.3948-3958

04/02/2019

DOI: 10.1021/acs.est.9b00535

PMCID: PMC6457253

PMID: 30821444

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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 [ H]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.

Pregnancy

Environmental Pollutants

Ryanodine Receptor Calcium Release Channel

Humans

Female

Serum

Polychlorinated Biphenyls

Receptors, Thyroid Hormone

Child

ISRP Project 3 2015-2020

Synthesis Core

UC-Davis collaboration

Details

Title: Subtitle: Comparative Analyses of the 12 Most Abundant PCB Congeners Detected in Human Maternal Serum for Activity at the Thyroid Hormone Receptor and Ryanodine Receptor
Creators: Sunjay Sethi - Department of Molecular Biosciences , University of California-Davis, School of Veterinary Medicine , Davis , California 95616 , United States
Rhianna K Morgan - Department of Molecular Biosciences , University of California-Davis, School of Veterinary Medicine , Davis , California 95616 , United States
Wei Feng - Department of Molecular Biosciences , University of California-Davis, School of Veterinary Medicine , Davis , California 95616 , United States
Yanping Lin - Department of Molecular Biosciences , University of California-Davis, School of Veterinary Medicine , Davis , California 95616 , United States
Xueshu Li - Department of Occupational & Environmental Health , University of Iowa , Iowa City , Iowa 52242 , United States
Corey Luna - Department of Molecular Biosciences , University of California-Davis, School of Veterinary Medicine , Davis , California 95616 , United States
Madison Koch - Department of Molecular Biosciences , University of California-Davis, School of Veterinary Medicine , Davis , California 95616 , United States
Ruby Bansal - Department of Biology , University of Massachusetts-Amherst , Amherst , Massachusetts 01003 , United States
Michael W Duffel - Department of Pharmaceutical Sciences and Experimental Therapeutics , University of Iowa , Iowa City , Iowa 52242 , United States
Birgit Puschner - Department of Molecular Biosciences , University of California-Davis, School of Veterinary Medicine , Davis , California 95616 , United States
R Thomas Zoeller - Department of Biology , University of Massachusetts-Amherst , Amherst , Massachusetts 01003 , United States
Hans-Joachim Lehmler - Department of Occupational & Environmental Health , University of Iowa , Iowa City , Iowa 52242 , United States
Isaac N Pessah - Department of Molecular Biosciences , University of California-Davis, School of Veterinary Medicine , Davis , California 95616 , United States
Pamela J Lein - Department of Molecular Biosciences , University of California-Davis, School of Veterinary Medicine , Davis , California 95616 , United States
Resource Type: Journal article
Publication Details: Environmental science & technology, Vol.53(7), pp.3948-3958
DOI: 10.1021/acs.est.9b00535
PMID: 30821444
PMCID: PMC6457253
NLM abbreviation: Environ Sci Technol
ISSN: 0013-936X
eISSN: 1520-5851
Publisher: United States
Grant note: P30 ES005605 / NIEHS NIH HHS P42 ES013661 / NIEHS NIH HHS P01 ES011269 / NIEHS NIH HHS P30 ES023513 / NIEHS NIH HHS T32 ES007059 / NIEHS NIH HHS R01 ES030318 / NIEHS NIH HHS R01 ES014901 / NIEHS NIH HHS
Language: English
Date published: 04/02/2019
Academic Unit: Occupational and Environmental Health; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Iowa Superfund Research Program; Medicinal and Natural Products Chemistry
Record Identifier: 9984000918602771

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