Abstract:Objective To analyze the intrauterine growth retardation (IUGR) and the changes of expressions of insulin receptor substrate-1 (IRS-1) and insulin receptor substrate-2 (IRS-2), the proteins of insulin signaling pathway, in liver and skeletal muscle of offspring fetal rats because of exposure to nicotine of pregnant rats and explore the related mechanism.? Methods Twenty-four Wistar rats 12 days after pregnancy were randomly divided into experiment group (hypodermic injection of nicotine of different doses, till 20 days after pregnancy) including small dose subgroup (0. 5 mg/kg, 2 ml, bid), mediumdose subgroup(1. 0 mg/kg, 2 ml, bid) and largedose subgroup (2. 0 mg/kg, 2 ml, bid) and control group (hypodermic injection of nicotine free normal saline of same volume, bid, till 20 days after pregnancy). At 20-day after rat pregnancy, fetal rats were taken out from mother′s body by caesarean after isoflurane anaesthesia to weigh and count the number and incidence of IUGR fetal rats in each group. Collecting the plasma of fetal rats in each group, adiponectin and corticosterone levels were detected by enzyme linked immunosorbent assay (ELISA) method. Isolating liver and skeletal muscle of fetal rats, the levels of IRS-1 mRNA and IRS-2 mRNA expressions were detected by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and real-time quantitative polymerase chain reaction (qRT-PCR), and the levels of IRS-1 protein and IRS-2 protein expressions were detected by Western blot method.? Results The weight of fetal rats after exposure to nicotine of different doses significantly decreased compared with control group (all P<0.05). The incidence of IUGR fetal rats for small, medium and large doses of nicotine were 14. 24%, 26. 35% and 75. 93%, respectively, and there was significant difference for comparison among groups (P<0.05). With the increase of nicotine concentration, weight of fetal rats decreased, and incidence of IUGR fetal rats increased in obvious dose-dependent manner. After exposure to nicotine of different doses, the concentration of plasma adiponectin of fetal rats decreased compared with control group (all P<0.05) , and the concentration of plasma corticosterone of fetal rats after exposure to nicotine of medium and large dosesincreased compared with control group in dose-dependent manner (all P<0.05). After exposure to nicotine of large doses, the expression levels of IRS-2 mRNA and IRS-2 protein in liver of fetal rats decreased compared with control group (all P<0.05) , and expression levels of IRS-1 mRNA and IRS-1 protein in skeletal muscle of fetal rats decreased compared with control group (all P<0.05). Conclusion Nicotine exposure in pregnant rats could lead to the decrease of expression of IRS-2 mRNA and IRS-2 protein in liver and the decrease of expression levels of IRS-1 mRNA and IRS-1 protein in skeletal muscle of fetal rats and the changes of the glycolipid metabolic pathway of fetal rats further which will make a direct impact on the growth and development of fetal rats, and this may be one of the reasons of IUGR occurrence and insulin resistance occurrence after birth of fetal rats.