Species-specific differential AhR expression protects human neural progenitor cells against developmental neurotoxicity of PAHs.
BACKGROUND
Because of their lipophilicity, persistent organic pollutants (POPs) cross the human placenta, possibly affecting central nervous system development. Most POPs are known aryl hydrocarbon receptor (AhR) ligands and activators of AhR signaling. Therefore, AhR activation has been suggested to cause developmental neurotoxicity (DNT).


OBJECTIVE
We studied the effects of AhR ligands on basic processes of brain development in two comparative in vitro systems to determine whether AhR-activation is the underlying mechanism for reported DNT of POPs in humans.


METHODS
We employed neurosphere cultures based on human neural progenitor cells (hNPCs) and wild-type and AhR-deficient mouse NPCs (mNPCs) and studied the effects of different AhR agonists [3-methylcholanthrene (3-MC), benzo(a)pyrene [B(a)P], and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)] and an antagonist [3'-methoxy-4'-nitroflavone (MNF)] on neurosphere development. Moreover, we analyzed expression of AhR and genes involved in AhR signaling.


RESULTS
In contrast to wild-type mNPCs, hNPCs and AhR-deficient mNPCs were insensitive to AhR agonism or antagonism. Although AhR modulation attenuated wild-type mNPC proliferation and migration, hNPCs and AhR-deficient mNPCs remained unaffected. Results also suggest that species-specific differences resulted from nonfunctional AhR signaling in hNPCs.


CONCLUSIONS
Our findings suggest that in contrast to wild-type mNPCs, hNPCs were protected against polycyclic aromatic hydrocarbon-induced DNT because of an absence of AhR This difference may contribute to species-specific differences in sensitivity to POPs.
Gassmann
Kathrin
K
Department of Molecular Toxicology, Institut für umweltmedizinische Forschung gGmbH, Heinrich Heine University, Düsseldorf, Germany.
Abel
Josef
J
Bothe
Hanno
H
Haarmann-Stemmann
Thomas
T
Merk
Hans F
HF
Quasthoff
Kim N
KN
Rockel
Thomas Dino
TD
Schreiber
Timm
T
Fritsche
Ellen
E
D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity; D002478:Cells, Cultured; D004785:Environmental Pollutants / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008748:Methylcholanthrene / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009420:Nervous System / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism
D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D011084:Polycyclic Aromatic Hydrocarbons; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D001564:Benzo(a)pyrene; D008748:Methylcholanthrene