Inherent and benzo[a]pyrene-induced differential aryl hydrocarbon receptor signaling greatly affects life span, atherosclerosis, cardiac gene expression, and body and heart growth in mice.
Little is known of the environmental factors that initiate and promote disease. The aryl hydrocarbon receptor (AHR) is a key regulator of xenobiotic metabolism and plays a major role in gene/environment interactions. The AHR has also been demonstrated to carry out critical functions in development and disease. A qualitative investigation into the contribution by the AHR when stimulated to different levels of activity was undertaken to determine whether AHR-regulated gene/environment interactions are an underlying cause of cardiovascular disease. We used two congenic mouse models differing at the Ahr gene, which encodes AHRs with a 10-fold difference in signaling potencies. Benzo[a]pyrene (BaP), a pervasive environmental toxicant, atherogen, and potent agonist for the AHR, was used as the environmental agent for AHR activation. We tested the hypothesis that activation of the AHR of different signaling potencies by BaP would have differential effects on the physiology and pathology of the mouse cardiovascular system. We found that differential AHR signaling from an exposure to BaP caused lethality in mice with the low-affinity AHR, altered the growth rates of the body and several organs, induced atherosclerosis to a greater extent in mice with the high-affinity AHR, and had a huge impact on gene expression of the aorta. Our studies also demonstrated an endogenous role for AHR signaling in regulating heart size. We report a gene/environment interaction linking differential AHR signaling in the mouse to altered aorta gene expression profiles, changes in body and organ growth rates, and atherosclerosis.
Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756, USA.
Joanna S
JS
Kerley-Hamilton
Heidi W
HW
Trask
Christian J A
CJ
Ridley
Eric
E
Dufour
Corina
C
Lesseur
Carol S
CS
Ringelberg
Karen L
KL
Moodie
Samantha L
SL
Shipman
Murray
M
Korc
Jiang
J
Gui
Nicholas W
NW
Shworak
Craig R
CR
Tomlinson
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism*; D001564:Benzo(a)pyrene / Q000633:toxicity*; D001835:Body Weight; D005786:Gene Expression Regulation / Q000187:drug effects*; D006128:Growth; D006321:Heart / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D008136:Longevity / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009206:Myocardium / Q000378:metabolism*; D009929:Organ Size; D016133:Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D001057:Apolipoproteins E; D018836:Inflammation Mediators; D018336:Receptors, Aryl Hydrocarbon; D001564:Benzo(a)pyrene