title: Species-specific differential AhR expression protects human neural progenitor cells against developmental neurotoxicity of PAHs.
abstract: 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.
authors.affiliation: Department of Molecular Toxicology, Institut für umweltmedizinische Forschung gGmbH, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Gassmann
authors.forename: Josef
authors.initials: J
authors.lastname: Abel
authors.forename: Hanno
authors.initials: H
authors.lastname: Bothe
authors.forename: Thomas
authors.initials: T
authors.lastname: Haarmann-Stemmann
authors.forename: Hans F
authors.initials: HF
authors.lastname: Merk
authors.forename: Kim N
authors.initials: KN
authors.lastname: Quasthoff
authors.forename: Thomas Dino
authors.initials: TD
authors.lastname: Rockel
authors.forename: Timm
authors.initials: T
authors.lastname: Schreiber
authors.forename: Ellen
authors.initials: E
authors.lastname: Fritsche
mesh_terms: 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
chemical_list: D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D011084:Polycyclic Aromatic Hydrocarbons; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D001564:Benzo(a)pyrene; D008748:Methylcholanthrene