Direct assessment of cumulative aryl hydrocarbon receptor agonist activity in sera from experimentally exposed mice and environmentally exposed humans

Jennifer J Schlezinger, Pamela L Bernard, Amelia Haas, Philippe Grandjean, Pal Weihe, David H Sherr

Publikation: Bidrag til tidsskriftTidsskriftartikelForskning

Resumé

BACKGROUND: Aryl hydrocarbon receptor (AhR) ligands adversely affect many biological processes. However, assessment of the significance of human exposures is hampered by an incomplete understanding of how complex mixtures affect AhR activation/inactivation. OBJECTIVES: These studies used biological readouts to provide a broader context for estimating human risk than that obtained with serum extraction and gas chromatography/mass spectroscopy (GC/MS)-based assays alone. METHODS: AhR agonist activity was quantified in sera from dioxin-treated mice, commercial human sources, and polychlorinated biphenyl (PCB)-exposed Faroe Islanders using an AhR-driven reporter cell line. To validate relationships between serum AhR agonist levels and biological outcomes, AhR agonist activity in mouse sera correlated with toxic end points. AhR agonist activity in unmanipulated ("neat") human sera was compared with these biologically relevant doses and with GC/MS-assayed PCB levels. RESULTS: Mouse serum AhR agonist activity correlated with injected dioxin dose, thymic atrophy, and heptomegaly, validating the use of neat serum to assess AhR agonist activity. AhR agonist activity in sera from Faroe Islanders varied widely, was associated with the frequency of recent pilot whale dinners, but did not correlate with levels of PCBs quantified by GC/MS. Surprisingly, significant "baseline" AhR activity was found in commercial human sera. CONCLUSIONS: An AhR reporter assay revealed cumulative levels of AhR activation potential in neat serum, whereas extraction may preclude detection of important non-dioxin-like biological activity. Significant levels of AhR agonist activity in commercial sera and in Faroe Islander sera, compared with that from experimentally exposed mice, suggest human exposures that are biologically relevant in both populations.
OriginalsprogEngelsk
TidsskriftEnvironmental Health Perspectives
Vol/bind118
Udgave nummer5
Sider (fra-til)693-8
Antal sider6
ISSN0091-6765
DOI
StatusUdgivet - 1. maj 2010

Fingeraftryk

Aryl Hydrocarbon Receptors
Serum
Gas Chromatography
Dioxins
Pilot Whales
Poisons
Complex Mixtures
Meals

Citer dette

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title = "Direct assessment of cumulative aryl hydrocarbon receptor agonist activity in sera from experimentally exposed mice and environmentally exposed humans",
abstract = "BACKGROUND: Aryl hydrocarbon receptor (AhR) ligands adversely affect many biological processes. However, assessment of the significance of human exposures is hampered by an incomplete understanding of how complex mixtures affect AhR activation/inactivation. OBJECTIVES: These studies used biological readouts to provide a broader context for estimating human risk than that obtained with serum extraction and gas chromatography/mass spectroscopy (GC/MS)-based assays alone. METHODS: AhR agonist activity was quantified in sera from dioxin-treated mice, commercial human sources, and polychlorinated biphenyl (PCB)-exposed Faroe Islanders using an AhR-driven reporter cell line. To validate relationships between serum AhR agonist levels and biological outcomes, AhR agonist activity in mouse sera correlated with toxic end points. AhR agonist activity in unmanipulated ({"}neat{"}) human sera was compared with these biologically relevant doses and with GC/MS-assayed PCB levels. RESULTS: Mouse serum AhR agonist activity correlated with injected dioxin dose, thymic atrophy, and heptomegaly, validating the use of neat serum to assess AhR agonist activity. AhR agonist activity in sera from Faroe Islanders varied widely, was associated with the frequency of recent pilot whale dinners, but did not correlate with levels of PCBs quantified by GC/MS. Surprisingly, significant {"}baseline{"} AhR activity was found in commercial human sera. CONCLUSIONS: An AhR reporter assay revealed cumulative levels of AhR activation potential in neat serum, whereas extraction may preclude detection of important non-dioxin-like biological activity. Significant levels of AhR agonist activity in commercial sera and in Faroe Islander sera, compared with that from experimentally exposed mice, suggest human exposures that are biologically relevant in both populations.",
keywords = "Animals, Cell Line, Cohort Studies, Denmark, Environmental Exposure, Environmental Pollutants, Female, Humans, Ligands, Mice, Mice, Inbred C57BL, Polychlorinated Biphenyls, Pregnancy, Receptors, Aryl Hydrocarbon, Risk Assessment, Tetrachlorodibenzodioxin",
author = "Schlezinger, {Jennifer J} and Bernard, {Pamela L} and Amelia Haas and Philippe Grandjean and Pal Weihe and Sherr, {David H}",
year = "2010",
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doi = "10.1289/ehp.0901113",
language = "English",
volume = "118",
pages = "693--8",
journal = "Environmental Health Perspectives",
issn = "0091-6765",
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Direct assessment of cumulative aryl hydrocarbon receptor agonist activity in sera from experimentally exposed mice and environmentally exposed humans. / Schlezinger, Jennifer J; Bernard, Pamela L; Haas, Amelia; Grandjean, Philippe; Weihe, Pal; Sherr, David H.

I: Environmental Health Perspectives, Bind 118, Nr. 5, 01.05.2010, s. 693-8.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskning

TY - JOUR

T1 - Direct assessment of cumulative aryl hydrocarbon receptor agonist activity in sera from experimentally exposed mice and environmentally exposed humans

AU - Schlezinger, Jennifer J

AU - Bernard, Pamela L

AU - Haas, Amelia

AU - Grandjean, Philippe

AU - Weihe, Pal

AU - Sherr, David H

PY - 2010/5/1

Y1 - 2010/5/1

N2 - BACKGROUND: Aryl hydrocarbon receptor (AhR) ligands adversely affect many biological processes. However, assessment of the significance of human exposures is hampered by an incomplete understanding of how complex mixtures affect AhR activation/inactivation. OBJECTIVES: These studies used biological readouts to provide a broader context for estimating human risk than that obtained with serum extraction and gas chromatography/mass spectroscopy (GC/MS)-based assays alone. METHODS: AhR agonist activity was quantified in sera from dioxin-treated mice, commercial human sources, and polychlorinated biphenyl (PCB)-exposed Faroe Islanders using an AhR-driven reporter cell line. To validate relationships between serum AhR agonist levels and biological outcomes, AhR agonist activity in mouse sera correlated with toxic end points. AhR agonist activity in unmanipulated ("neat") human sera was compared with these biologically relevant doses and with GC/MS-assayed PCB levels. RESULTS: Mouse serum AhR agonist activity correlated with injected dioxin dose, thymic atrophy, and heptomegaly, validating the use of neat serum to assess AhR agonist activity. AhR agonist activity in sera from Faroe Islanders varied widely, was associated with the frequency of recent pilot whale dinners, but did not correlate with levels of PCBs quantified by GC/MS. Surprisingly, significant "baseline" AhR activity was found in commercial human sera. CONCLUSIONS: An AhR reporter assay revealed cumulative levels of AhR activation potential in neat serum, whereas extraction may preclude detection of important non-dioxin-like biological activity. Significant levels of AhR agonist activity in commercial sera and in Faroe Islander sera, compared with that from experimentally exposed mice, suggest human exposures that are biologically relevant in both populations.

AB - BACKGROUND: Aryl hydrocarbon receptor (AhR) ligands adversely affect many biological processes. However, assessment of the significance of human exposures is hampered by an incomplete understanding of how complex mixtures affect AhR activation/inactivation. OBJECTIVES: These studies used biological readouts to provide a broader context for estimating human risk than that obtained with serum extraction and gas chromatography/mass spectroscopy (GC/MS)-based assays alone. METHODS: AhR agonist activity was quantified in sera from dioxin-treated mice, commercial human sources, and polychlorinated biphenyl (PCB)-exposed Faroe Islanders using an AhR-driven reporter cell line. To validate relationships between serum AhR agonist levels and biological outcomes, AhR agonist activity in mouse sera correlated with toxic end points. AhR agonist activity in unmanipulated ("neat") human sera was compared with these biologically relevant doses and with GC/MS-assayed PCB levels. RESULTS: Mouse serum AhR agonist activity correlated with injected dioxin dose, thymic atrophy, and heptomegaly, validating the use of neat serum to assess AhR agonist activity. AhR agonist activity in sera from Faroe Islanders varied widely, was associated with the frequency of recent pilot whale dinners, but did not correlate with levels of PCBs quantified by GC/MS. Surprisingly, significant "baseline" AhR activity was found in commercial human sera. CONCLUSIONS: An AhR reporter assay revealed cumulative levels of AhR activation potential in neat serum, whereas extraction may preclude detection of important non-dioxin-like biological activity. Significant levels of AhR agonist activity in commercial sera and in Faroe Islander sera, compared with that from experimentally exposed mice, suggest human exposures that are biologically relevant in both populations.

KW - Animals

KW - Cell Line

KW - Cohort Studies

KW - Denmark

KW - Environmental Exposure

KW - Environmental Pollutants

KW - Female

KW - Humans

KW - Ligands

KW - Mice

KW - Mice, Inbred C57BL

KW - Polychlorinated Biphenyls

KW - Pregnancy

KW - Receptors, Aryl Hydrocarbon

KW - Risk Assessment

KW - Tetrachlorodibenzodioxin

U2 - 10.1289/ehp.0901113

DO - 10.1289/ehp.0901113

M3 - Journal article

VL - 118

SP - 693

EP - 698

JO - Environmental Health Perspectives

JF - Environmental Health Perspectives

SN - 0091-6765

IS - 5

ER -