| Background Tobacco exposure is associated with cardiovascular disease, nicotineis the main causative ingredients in tobacco. The intrauterine environment in early lifecan make imprints to fetuses, and program cardiovascular diseases in their later life.Endothelial dysfunction and IGFs axis abnormalities are involved in the developmentof cardiovascular disease. However, it is still unclear that the effects of prenatalnicotine exposure (PNE) on endothelial function and IGFs Axis in the adult offspring.Objective This study was designed to elucidate the role of PNE on endothelialfunction and IGFs axis in rat offspring and the potential gender dependent differencesof it, and to clarify whether these effects persist into adult life.Methods20pregnant Sprague-Dawley rats were randomly divided into two groups:PNE group and the normal control group. The rats were exposed to nicotine (8mg/kg/day) for PNE group or saline for the controls via subcutaneous osmoticmini-pumps (2ML4) throughout the gestation. At age5-month, offspring rats wereintraperitoneal anesthesia and their thoracic aorta and mesenteric arteries, hearts,lungs, livers, kidneys, pancreas and blood were sampled for analysis. Vascularendothelial function was detected in the thoracic aorta and mesenteric arteries withPower Lab data acquisition and analysis system. Serum IGF-1, IGF-2, IGFBP-1,IGFBP-2and IGFBP-3levels were measured by enzyme-linked immunosorbnentassay (ELISA). Pathomorphology changes of aorta, heart, lung, liver, kidney andpancreas were determined by Hematoxylin-Eosin (HE) staining and the proteinexpressions of IGF-1, IGF-1R, IGF-2, IGFBP-1, IGFBP-2and IGFBP-3in theabove-mentioned tissues were examined by immunohistochemistry staining.Results1) There were no significant differences of endothelium-dependent/-independentvasodilatation percentages in the thoracic aorta from offspring after exposure toAch/SNP between PNE and control group (all P>0.05). 2) Ach/SNP induced endothelium-dependent/-independent vasodilatationpercentages in mesenteric artery were significantly lower in PNE male offspringthan those of controls (all P <0.05), while significantly higher in PNE female (allP <0.05).3) The uneven lumen, degenerated and partial loss of endothelial cells, thickenedintima, markedly atrophied medial smooth muscle and disorganized elastic fiberwere found in the thoracic aorta from PNE offspring by HE staining. Lymphoidfollicles and inflammatory cells infiltration in alveolar interstitium around thebronchia and dilated arterioles around the glomerulis were observed in PNEoffspring. However, the above pathological changes were not found in thecontrols.4) Serum IGFBP-3levels were significantly declined in female PNE offspring ascompared with the controls (P <0.05), but not in the male PNE offspring (P>0.05). Moreover, there were no significant difference of serum IGF-1, IGF-2,IGFBP-1and IGFBP-2levels between PNE and control group (all P>0.05).5) Samples of normal control offsprings, the expressions of IGF-1, IGF-1R, IGF-2,IGFBP-1, IGFBP-2and IGFBP-3were expressed strongly in the kidneys frommale controls (+++), whereas weakly in female ones (±~+). However, theirexpressions were down-regulated in male PNE offsprings (+~++) andup-regulated in female (+~++) as compared with controls. The expression ofIGF-1, IGF-1R, IGF-2, IGFBP-1, IGFBP-2and IGFBP-3were weak (±~+) inliver from normal controls, and up-regulated in PNE offsprings (+++). Therewas marginal expression (±) in small arteries surround Alveolar interstitium fromPNE offsprings, but not in the controls. While in organs or tissues of pancreas,heart and thoracic aorta, all of the above IGFs were not expressed both in PNEand control group.Conclusions1) PNE can affect mesenteric artery endothelium-dependent/-independentvasodilation in5-month-old rats offspring with a gender dependent charecter,indicating that endothelial dysfunction induced by PNE initiates in medium-size muscularartery and persists into adult life, and is more susceptible in the maleoffsprings than females.2) PNE causes thoracic aorta intimal and medial pathologic structural damages in5-month-old offspring, suggesting that PNE not only induces vasculardysfunction but also leads to pathological structure changes. Additionally, it alsoresults in lymphoid follicles and inflammatory cells infiltration in alveolarinterstitium around the bronchia.3) PNE down-regulates serum IGFBP-3levels in5-month old female offspring rats,and causes abnormal tissue-specific expression of IGFs and IGFBPs in theoffsprings. Their expressions in kidneys are different between male and femaleoffsprings. Regulation of offspring IGFs axis by PNE may mediate PNE inducedendothelial dysfunction. |
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