title: Transient exposure of neonatal female mice to testosterone abrogates the sexual dimorphism of abdominal aortic aneurysms.
abstract: BACKGROUND
  Abdominal aortic aneurysms (AAAs) exhibit marked sexual dimorphism with higher prevalence in men. Similarly, AAAs induced by angiotensin II (AngII) infusion into mice exhibit a higher prevalence in males. Testosterone promotes AAA pathology in adult male mice through regulation of angiotensin type 1A receptors (AT1aR) in abdominal aortas. However, mechanisms for sexual dimorphism of regional aortic angiotensin receptor expression and AAA formation are unknown.
  
  
  OBJECTIVE
  To define the role of developmental testosterone exposures in sexual dimorphism of AAAs, we determined if exposure of neonatal female mice to testosterone confers adult susceptibility to AngII-induced AAAs.
  
  
  RESULTS
  One-day-old female hypercholesterolemic mice were administered a single dose of either vehicle or testosterone. Neonatal testosterone administration increased abdominal aortic AT1aR mRNA abundance and promoted a striking increase in AngII-induced AAAs in adult females exhibiting low serum testosterone concentrations. AngII-induced atherosclerosis and ascending aortic aneurysms were also increased by testosterone administration to neonatal females. In contrast, neonatal testosterone administration in males had no effect on AngII-induced vascular pathologies. Deficiency of AT1aR in smooth muscle cells reduced effects of neonatal testosterone to promote AAAs in adult females but did not alter atherosclerosis or ascending aortic aneurysms. Testosterone increased AT1aR mRNA abundance and hydrogen peroxide generation in cultured abdominal aortic SMCs. Increased AT1aR mRNA abundance was maintained during progressive passaging of female smooth muscle cells.
  
  
  CONCLUSIONS
  These data reveal an unrecognized role of transient sex hormone exposures during neonatal development as long-lasting mediators of regional aortic AT1aR expression and sexual dimorphism of AAAs.
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536-0200, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Sean E
authors.initials: SE
authors.lastname: Thatcher
authors.forename: Debra L
authors.initials: DL
authors.lastname: Rateri
authors.forename: Dennis
authors.initials: D
authors.lastname: Bruemmer
authors.forename: Richard
authors.initials: R
authors.lastname: Charnigo
authors.forename: Alan
authors.initials: A
authors.lastname: Daugherty
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cassis
mesh_terms: D000367:Age Factors; D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D001012:Aorta, Abdominal / Q000378:metabolism* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000139:chemically induced / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D012727:Sex Characteristics; D012737:Sex Factors; D043343:Testosterone Propionate / Q000008:administration & dosage / Q000633:toxicity*; D015854:Up-Regulation
chemical_list: C544066:Agtr1a protein, mouse; D001057:Apolipoproteins E; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011973:Receptors, LDL; D000804:Angiotensin II; D006861:Hydrogen Peroxide; D043343:Testosterone Propionate