Fetal growth restriction triggered by polycyclic aromatic hydrocarbons is associated with altered placental vasculature and AhR-dependent changes in cell death.
Maternal cigarette smoking is considered an important risk factor associated with fetal intrauterine growth restriction (IUGR). Polycyclic aromatic hydrocarbons (PAHs) are well-known constituents of cigarette smoke, and the effects of acute exposure to these chemicals at different gestational stages have been well established in a variety of laboratory animals. In addition, many PAHs are known ligands of the aryl hydrocarbon receptor (AhR), a cellular xenobiotic sensor responsible for activating the metabolic machinery. In this study, we have applied a chronic, low-dose regimen of PAH exposure to C57Bl/6 female mice before conception. This treatment caused IUGR in day 15.5 post coitum (d15.5) fetuses and yielded abnormalities in the placental vasculature, resulting in significantly reduced arterial surface area and volume of the fetal arterial vasculature of the placenta. However, examination of the small vasculature within the placental labyrinth of PAH-exposed dams revealed extensive branching and enlargement of these vessels, indicating a possible compensatory mechanism. These alterations in vascularization were accompanied by reduced placental cell death rates, increased expression levels of antiapoptotic Xiap, and decreased expression of proapoptotic Bax, cleaved poly(ADP-ribose) polymerase-1, and active caspase-3. AhR-deficient fetuses were rescued from PAH-induced growth restriction and exhibited no changes in the labyrinthine cell death rate. The results of this investigation suggest that chronic exposure to PAHs is a contributing factor to the development of IUGR in human smokers and that the AhR pathway is involved.
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada.
Jacqui
J
Detmar
Monique Y
MY
Rennie
Kathie J
KJ
Whiteley
Dawei
D
Qu
Yoshinari
Y
Taniuchi
Xueyuan
X
Shang
Robert F
RF
Casper
S Lee
SL
Adamson
John G
JG
Sled
Andrea
A
Jurisicova
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D005260:Female; D005317:Fetal Growth Retardation / Q000139:chemically induced* / Q000378:metabolism; D006651:Histocytochemistry; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D010920:Placenta / Q000098:blood supply* / Q000187:drug effects*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D011247:Pregnancy; D011897:Random Allocation; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D053148:Caspase 3; D011065:Poly(ADP-ribose) Polymerases; D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; D051636:X-Linked Inhibitor of Apoptosis Protein; D051028:bcl-2-Associated X Protein; C484722:Ahr protein, mouse; C505409:Casp3 protein, mouse