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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)3948-3958
Number of pages11
JournalEnvironmental Science and Technology
Volume53
Issue number7
DOIs
StatePublished - Apr 2 2019

Fingerprint

Thyroid Hormone Receptors
Ryanodine Receptor Calcium Release Channel
Polychlorinated Biphenyls
hormone
serum
PCB
Ryanodine
Environmental Pollutants
Metabolites
Gas chromatography
Risk assessment
Sulfates
Mass spectrometry
brain
Assays
Brain
metabolite
gas chromatography
Screening
risk assessment

ASJC Scopus subject areas

  • Chemistry(all)
  • Environmental Chemistry

Cite this

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

In: Environmental Science and Technology, Vol. 53, No. 7, 02.04.2019, p. 3948-3958.

Research output: Contribution to journalArticle

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. / Comparative Analyses of the 12 Most Abundant PCB Congeners Detected in Human Maternal Serum for Activity at the Thyroid Hormone Receptor and Ryanodine Receptor. In: Environmental Science and Technology. 2019 ; Vol. 53, No. 7. pp. 3948-3958.
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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 [ 3 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.",
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AU - Feng, Wei

AU - Lin, Yanping

AU - Li, Xueshu

AU - Luna, Corey

AU - Koch, Madison

AU - Bansal, Ruby

AU - Duffel, Michael W.

AU - Puschner, Birgit

AU - Zoeller, R. Thomas

AU - Lehmler, Hans Joachim

AU - Pessah, Isaac N

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N2 - 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 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.

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