Effects of oxytocin treatment early in pregnancy on fetal growth in ad libitum-fed and food-restricted rats.

The effects of oxytocin on fetal and placental growth and on maternal weight gain and accumulation of body fat were studied in ad libitum-fed and food-restricted (receiving 70% of the food intake of the ad libitum-fed group) pregnant rats. Further, a possible role of the IGF axis in mediating oxytocin-induced changes was assessed. Pregnant rats were injected subcutaneously once a day during gestational d 1-5 with saline or oxytocin (1 mg/kg). Ad libitum-fed oxytocin-treated pregnant rats had higher circulating levels of IGF-I, larger placentas, fetuses, and newborn pups and contained less body fat at the end of pregnancy. In food-restricted dams, oxytocin-treatment had no effect on fetal and placental growth. Additionally, food restriction attenuated the normal increase in IGF binding protein-3 protease proteolysis during pregnancy. The results show that oxytocin may affect maternal adaptations to pregnancy and stimulate fetal growth. We suggest that this effect may be mediated by increased IGF-I in ad libitum-fed animals, whereas food restriction may block this effect by resulting in low levels of circulating IGF-I and by attenuating the pregnancy-associated increase in IGF binding protein-3 protease activity and, thereby, further compromise IGF bioavailability.     

Teratogenicity of Azosemide, a Loop Diuretic, in Rats, Mice and Rabbits

Teratogenic effects of azosemide, a loop diuretic, were investigated in rats, mice and rabbits. Azosemide was given orally to pregnant rats, mice and rabbits during organogenesis. The pregnant animals were killed at term and their fetuses were examined for external, visceral and skeletal abnormalities. In rats, azosemide at 10–30 mg/kg/day did not affect intrauterine growth, resorptions and rates of external and visceral malformations. Treatment with 90 mg/kg/day resulted in a significant increase in skeletal abnormalities such as wavy ribs, bent scapula and bent humerus. However, the skeletal abnormalities observed in term fetuses could not be found in adult offspring, indicating that they were temporary. In mice, 1250 mg/kg/day of azosemide caused maternal death, abortion, and retarded maternal and fetal weight. Treatment with 200–500 mg/kg/day did not induce fetal mortalities, external and visceral malformations. Skeletal abnormalities increased in dose-dependent fashion. The type of abnormalities was identical to that encountered in rat fetuses. Furosemide as a positive control also produced similar types of skeletal abnormalities in mouse fetuses. In rabbits, azosemide did not have embryolethal or teratogenic effects even at the highest dose (6 mg/kg/ day), which caused maternal death. Treatment for a different 3-day period and then a different day during organogenesis in rats and mice showed that the sensitive period was days 15–17 of gestation with a peak on day 16 in rats, and days 12–15 with a peak on day 13 in mice.     

Prenatal developmental toxicity studies of 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (p, p'-DDT) in rats and rabbits

ABSTRACT  The studies were conducted in rats and rabbits to elucidate the potential developmental toxicity of p, p '-DDT in general accordance with the improved Japanese MAFF guidelines (12-Nousan-No. 8147,2–1–18, 2000). p, p '-DDT suspended in 1% aqueous solution of CMC was administered orally to pregnant Jcl:SD rats on gestational days (GD) 6–19 at a dose of 0,5, 25, or 100 mg/kg/day and to pregnant KbI: JW rabbits on GD 6–27 at a dose of 0,5,20, or 80 mg/kg/day. Maternal animals were killed on the day after the last day of administration for morphological examination of their fetuses with special attention to the reproductive organs.
Adverse effects on maternal animals were found only at the highest dose in both species; i.e. , clonic convulsion (2/24 in rats, 5/22 in rabbits), mortality (1/24 in rats), abortion or premature delivery (4/22 in rabbits), and reduced body weight gains and food consumption. However, the control and treated groups showed comparable values for the numbers of corpora lutea and implants, percent preimplantation losses, number of live fetuses, percent resorptions and fetal deaths, sex ratio, fetal body weights, and placental weights in both species, and anogenital distance and testicular histology in rats. Although fetal examination revealed slightly increased incidence of 27 presacral vertebrae in the highest dose group in rats, there was no treatment-related increase in the incidence of malformations in any of the species.
Based on these results, it is concluded that p, p '-DDT causes no malformations, including male reproductive organ abnormalities, in either rats or rabbits, although it results in an increased incidence of skeletal variations in rats at a maternally toxic dose.     

Cardiovascular malformations associated with maternal hypoxia due to methemoglobinemia in aniline hydrochloride-treated rats

ABSTRACT  Aniline hydrochloride (AH), a methemoglobin-formation stimulating substance, at a dosage level that does not induce apparent fetal death was injected subcutaneously into pregnant rats once a day on days 6–8, 9–11, 12–14 or 15–17 of gestation in order to assess its ability to stage-specifically produce cardiovascular malformations. In addition, AH at dosage levels of 195, 260, 325 and 395 rag/kg was injected into pregnant rats subcutaneously once a day on days 12–14 of gestation, and the dose-dependent induction of ventricular septal defect (VSD) in relation to maternal methemoglobinemia was studied. In the stage-specificity study, paleness, decreased body weight gain and elevated methemoglobin concentration were noted in the dams. Upon fetal examination, reduced body weight was noted in all AH-treated groups. AH induced cardiovascular malformations, mainly VSD, which was most frequently observed in the day 12–14 group and also observed in the day 15–17 group. Abnormal branching of subclavian, pulmonary and vertebral arteries were most frequently observed in the day 9–11 group. In the dose-dependency study, AH induced maternal methemoglobinemia, decreased fetal body weight and increased the incidence of VSD dose dependency. Additionally, administration of methylene blue, a methemoglobinemia-preventing substance, to the AH-treated dams ameliorated maternal methemoglobinemia and reduced the incidence of fetal VSD. From these results, it is considered that AH stage-specifically induces cardiovascular defects, mainly VSD, in rats and that VSD is induced not by a direct teratogenic effect of AH but by maternal hypoxia due to methemoglobinemia.     

Induction of cleft palate in aniline hydrochloride-treated rats: Possible effect of maternal methemoglobinemic hypoxia

ABSTRACT  Aniline hydrochloride (AH), a methemoglobin formation-stimulating substance, at a dosage level of 520 mg/kg which does not induce apparent fetal death, was injected subcutaneously into pregnant rats once on day 14, 15 or 16 of gestation in order to assess the stage specificity of cleft palate induction. Also, doses of 260, 390, 520 and 650 mg/kg were administered to pregnant rats on day 15 of gestation, and the dose-response relationships with respect to fetal cleft palate and maternal methemo-globinemia induction were studied. In the stage-specificity study, paleness, decreased body weight gain and elevated methemoglobin concentration were noted in the dams treated with AH. Upon fetal examinations, although reduced body weight was noted in all AH-treated groups, cleft palate was observed only in fetuses from those dams treated on day 15 of gestation. In the dose-dependency study, AH induced maternal methemoglobinemia, decreased fetal body weight and increased the incidence of cleft palate dose dependently when administered at dosage levels of 260, 390, 520 and 650 mg/kg on day 15 of gestation. Additionally, administration of methylene blue, a methemoglobinemia-preventing substance, to the AH-treated dams ameliorated maternal methemoglobinemia and reduced the incidence of fetal cleft palate. In summation, it is considered that AH stage-specifically induces cleft palate in rats and that cleft palate is caused not by a direct teratogenic effect of AH but by maternal hypoxia due to methemoglobinemia.     

The effects of maternal hyperoxia on fetal breathing movements, body movements and heart rate variation in growth retarded fetuses.

In hypoxemic intrauterine growth-retarded fetuses (IUGR) there is a reduction in the incidence of fetal movements and in fetal heart rate variation. A causal relationship with the impairment of fetal oxygenation has been suggested. In 16 IUGR fetuses and in 13 normally grown fetuses maternal hyperoxygenation was applied for 40 min to increase fetal PO2 levels. All IUGR fetuses had abnormal Doppler blood velocity waveforms of the umbilical artery suggesting an impaired uteroplacental exchange. The effect of hyperoxygenation on fetal breathing and body movements and on fetal heart rate was evaluated. In the IUGR fetuses there was a significant increase in fetal breathing and body movements and in heart rate variation during hyperoxygenation as compared to the preceding control period of 40 min. No significant changes in fetal breathing and body movements were found in the normally grown control fetuses. A surprising observation was the increase of the number of heart rate decelerations after discontinuation of the maternal hyperoxygenation. It is concluded that in IUGR fetuses the increase in fetal heart rate variation and the increase in the incidence of breathing and body movements during maternal hyperoxygenation substantiates the relationship between these variables and the oxygenation status of the fetus.     

表没食子儿茶素-3-没食子酸酯对宫内生长受限大鼠肝脏脂代谢的影响和机制

目的 探讨表没食子儿茶素-3-没食子酸酯（EGCG）对宫内生长受限（IUGR）大鼠肝脏脂代谢的影响和机制。方法 采用母鼠孕期全程限食法建立IUGR大鼠模型,随机分为IUGR组和EGCG组,EGCG组大鼠在离乳后用含EGCG的饮用水喂养至10周,同时设立正常对照组,每组8只。13周龄时,测量各组大鼠体重后,采集大鼠血液及肝脏组织标本,检测各组大鼠血清空腹总胆固醇（TC）、甘油三酯（TG）、游离脂肪酸（FFA）、血糖（FPG）、胰岛素（FINS）和肝脏脂质水平,计算稳态模型评估胰岛素抵抗（HOMA-IR）和脂肪组织胰岛素抵抗（adipo-IR）,观察肝脏组织病理切片,并采用实时荧光定量PCR法检测肝脏相关基因的相对表达水平。结果 13周龄时,各组大鼠体重比较差异无统计学意义（P=0.067）。各组间的FPG、FFA、FINS、HOMA-IR和adipo-IR水平比较差异均有统计学意义（P < 0.05）。各组间的血清TC和TG水平比较差异无统计学意义（P > 0.05）,但在肝脏中IUGR组TC和TG水平均明显高于EGCG组（P < 0.05）。油红染色结果提示,IUGR大鼠的肝脏脂肪储积明显增加,而EGCG能够改善该现象。PCR结果显示,与对照组相比,IUGR组的Ampk mRNA及Adipor1 mRNA表达水平降低,Srebf1 mRNA表达水平增加（P < 0.05）,EGCG能逆转IUGR大鼠Ampk mRNA及Srebf1 mRNA的表达水平,且与对照组比较差异无统计学意义（P > 0.05）。结论 早期EGCG干预可能通过Ampk/Srebf1通路下调脂肪酸的从头合成,并通过改善肝细胞的胰岛素抵抗,从而降低IUGR大鼠的肝脏脂肪积累。     

Plasma calcium control in the rat fetus. I. Influence of maternal hormones

The influence of PTH, calcitonin (CT), and thyroxine deficiencies during pregnancy on fetal plasma calcium and fetal growth has been investigated in thyroidectomized (TX) and thyroparathyroidectomized (TPTX) mother rats complemented or not with thyroxine. Maternal femurs analyses at 21.5 days of gestation in TX and TPTX rats showed a significant decrease in wet and dry weights, whereas percentage of ash and its relative content in calcium and phosphorus was unchanged. Thus, CT during pregnancy seemed to prevent a decrease in the organic part of bone. The fetus from TPTX mothers was characterized by a reduced body weight (-1.95 g) and a 12% drop in its percentage of ash. The length of the fetal femur was 16% decreased, the shaft being mainly affected. It the percentage of ash of the fetal femur was unchanged, its relative content in calcium and phosphorus was decreased. In fetuses from TX mothers, the body weight was slightly decreased (approximately 0.71 g) and the percentage of ash was 5% reduced. The small decrease in the fetal femur length reflected a change at the distal end. Thyroxine complementation in TX or TPTX mothers induced a normalization of the fetal percentage of ash in both cases; a trend towards an increased value was observed in the percentage of ash of fetal femurs. Fetuses from TX mothers exhibited normal plasma calcium values unaffected by maternal thyroxine complementation. The lowered plasma calcium level (approximately 2.5 mg/dl) occurring in fetuses from TPTX mothers was increased by 1 mg/dl after thyroxine complementation of the mother in spite of unaltered maternal plasma calcium levels.     

食物限制法建立宫内发育迟缓模型及对其重要器官的影响

目的比较孕鼠妊娠期不同阶段进行不同程度食物摄入限制对其新生仔鼠体格及重要器官发育的影响。方法将妊娠大鼠随机分为3个模型组和对照组。模型组分别予妊娠全程中度、妊娠后期重度、妊娠中后期重度食物摄入限制。比较各组新生仔鼠的体格发育及重要器官重量及活产小于胎龄(SGA)鼠的发生率。光镜下观察其大脑和胃黏膜组织细胞形态学变化。结果各模型组存活新生鼠体质量、身长、尾长、脑、心、肺、肝、胃、脾、肾重量与对照组比较均有统计学差异(P均<0.05)。妊娠全程中度食物限制法致新生仔鼠SGA发生率最高(62.2%)。模型组SGA鼠大脑和胃黏膜有明显组织细胞形态学变化。结论妊娠全程中度食物摄入限制法可获得较高的SGA发生率和活产率。孕期食物摄入限制可致新生仔鼠脑、胃等器官出现组织形态学变化。     

Effects of maternal starvation on hepatocyte proliferation in the late gestation fetal rat

Fetal growth retardation, a common end point for a variety of conditions affecting mother and fetus, is associated with reduced liver mass. We have performed studies to determine the mechanism for decreased liver mass in a maternal starvation model of fetal growth restriction in the rat. Pregnant dams were deprived of food for 48 h before delivery on embryonic day 19 (E19). Fetal body weight was not affected. However, fetal liver weight was reduced by approximately 15%. Immunostaining of fetal liver for proliferating cell nuclear antigen and flow cytometry on isolated fetal hepatocytes showed G1 cell cycle arrest in samples from starved dams. Based on our prior studies showing attenuated hepatic insulin signaling in the late gestation fetal rat, we tested the hypothesis that G1 arrest in our model might be due to altered nutrient signaling. Fetal plasma amino acid analyses showed no decrease in branched-chain amino acids, but arginine concentrations were decreased in fetuses of fasted mothers. Reduced arginine in E19 fetal hepatocyte culture media was associated with decreased DNA synthesis. Whereas levels of cyclins D and E were unchanged in fetal hepatocytes exposed to low arginine, cyclin E-dependent kinase activity was reduced. Low arginine also induced changes in the translational machinery, indicative of impaired signaling through the nutrient sensing kinase mammalian target of rapamycin. Our results are consistent with the hypothesis that restricted nutrient availability signals to the hepatocyte cell cycle in fetuses of fasted mothers, thereby accounting for decreased hepatocyte proliferation and liver mass.     

Effects of maternal bilateral adrenalectomy and betamethasone administration on fetal rat encephalic development

The present study examined the effects of maternal bilateral adrenalectomy and betamethasone treatment on fetal encephalic development, in terms of fetal body weight, brain weight, DNA, protein and lipid content and morphological development. Both influenced the developmental time patterns of fetal brain and cerebellum. Fetuses of adrenalectomized rats had decreased body weights, whereas brain weight was not affected. Maternal adrenalectomy produces in fetal brain a decreased number of cells and increased cell size, while betamethasone treatment of adrenalectomized rats increased cell number, which was not different from control values; cell size remained lower than in control fetuses. Lipid content was increased in the fetuses of betamethasone-treated rats. In terms of morphological development, laminated structures (hippocampus and brain and cerebellar cortex) were the ones most affected.     

Restraint-induced maternal stress and alteration of ossification in mouse fetuses

Jcl:ICR pregnant mice were immobilized for 120 minutes from days 8–12 of gestation, and their fetuses were examined for skeletal features on day 18 of gestation. In the stressed group, decreased maternal bodyweight gain and lower fetal weight were noted. In this group, the incidences of segmentation defects, fused ribs, absent lumbar vertebrae and full supernumerary ribs were increased in fetuses. In addition, fusion of the basi- and ex-occipital bones was frequently observed in this group (12.9%). This finding was seen at an incidence of 1.4% in the control group, usually in newborns during the ossification process of the occipital bone. Therefore, the fused basi- and ex-occipital bones were considered to be due to altered ossification, but not to be an abnormality. In summary, immobilization of Jcl:ICR mice during the period of fetal organogenesis induced altered ossification of the occipital bones as well as some abnormalities and supernumerary ribs.     

Effect of a maternal fast on the urea cycle enzymes of the ovine fetus

Activities of five urea cycle enzymes were measured in maternal and fetal sheep liver during the normal fed state and following 5 days of fasting. Six ewes and 10 fetuses were studied in both the fed and fasted periods at 132 days gestation (term: 147 days) for liver protein and enzyme levels. Results indicated that protein content increased during fasting in both the maternal and fetal liver. Fetal liver weight was decreased during fasting from 108 +/- 8.5 to 71 +/- 8.2 g (mean +/- SD) (p less than 0.001). Fed state fetal enzyme activities per gram liver were 50-125% of maternal values. After fasting, four of the five fetal enzymes increased approximately twofold to fivefold (per gram tissue) (ornithine transcarbamylase did not change). Only one enzyme (argininosuccinase) increased significantly in maternal liver. Total liver activities gave similar results. These data indicate that the in vivo studies that demonstrate a doubling in fetal urea production in the fasted sheep in later gestation are associated with parallel increases in the fetal hepatic activities of several enzymes that are responsible for urea synthesis.     

Impact of maternal food restriction on cold-induced thermogenesis in the offspring

Food restriction imposed during pregnancy usually leads to many alterations in the development of the conceptus. Some of these alterations can be reverted after birth by adequate nutritional rehabilitation, while there are others which are permanent. The aim of this article is to study the influence of maternal food restriction on offspring thermoregulation. Offspring of dams with food restriction during pregnancy (50%) were fed ad libitum after weaning. Rectal temperature was measured every 15 days from weaning to the 90th day of life. From the 60th to the 90th day the animals were either acclimated at 25 or 5 degrees C. On the 90th day the animals were killed and their carcasses were processed for energy balance analysis and body composition determination. The results showed that animals from food-restricted mothers were not able to maintain body temperature for a longer period of time than the pups from control dams. Energy balance parameters and body composition did not show significant differences between rats from control and food-restriction mothers at the same environmental temperature. Thus, the results suggest that intrauterine food restriction may delay the development of the hypothalamus-thyroid axis which, in turn, may affect brown adipose tissue development leading to inefficient thermoregulation during neonatal life.     

Maternal nutrient restriction reduces carotid artery constriction without increasing nitric oxide synthesis in the late gestation rat fetus

Chronic reduction in substrate delivery to the fetus may induce redistribution of fetal cardiac output to maintain nutrient delivery to vital organs, including the brain. Reduced vasoconstriction, in conjunction with increased local synthesis of nitric oxide may contribute to "brain sparing." The authors hypothesized that maternal undernutrition would reduce vasoconstrictor responses in fetal carotid arteries due to increased nitric oxide. Timed pregnant Sprague-Dawley rats were randomized on day 0 of pregnancy to control (C) or nutrient restricted (NR) diet. Dams were killed on day 20 of pregnancy. Fetal carotid artery responses were assessed using a pressurized myograph system. Fetal body weight was reduced by NR diet. In NR fetuses, liver, lung, kidney, and heart weights were lower, whereas proportional brain weight was greater. Carotid artery constriction to endothelin-1 was similar in both groups; however, phenylephrine-induced constriction was decreased in NR arteries. Arteries from control fetuses constricted in response to increasing concentrations of L-NAME, whereas arteries from NR did not. There was also no effect of L-NAME on constriction to phenylephrine in arteries from NR fetuses. Our study indicates that the reduced carotid artery vasoconstriction to phenylephrine in NR fetuses, which is consistent with the maintenance of fetal brain blood flow, was not mediated by enhanced nitric oxide. Reduced phenylephrine but not endothelin-1-induced constriction suggests specific effects on adrenergic carotid artery function, which may implicate this pathway in the vascular adaptation to fetal undernutrition.     

Diabetes in pregnancy: decreased placental blood flow and disturbed fetal development in the rat

Placental blood flow was measured with the aid of radioactive microspheres, in normal (N) and manifest diabetic (MD) rats, and related to fetal body growth and incidence of congenital malformations. The total blood flow in the placentae of the MD rats was decreased to about one-half of the normal flow on gestational days 20 and 22. The placentae of the MD offspring were enlarged, whereas the fetuses in this group were smaller than normal. Thus, the placental blood flow per placental weight was drastically decreased in the MD fetuses on both days 20 and 22. In contrast, the placental blood flow per fetal weight was not different in the N and MD groups on gestational day 20 whereas it was decreased in the MD offspring on gestational day 22. Placental blood flow in the malformed fetuses of the MD group did not differ significantly from that in the nonmalformed MD fetuses.     

Fetal Heart Malformations in Experimental Hyperphenylalaninemia in Pregnant Rats

Abstract Sprague-Dawley rats were given L-phenylalanine intraperitoneally from the 8th to 11th day of pregnancy. The hearts of the fetuses were examined on the 21st day of pregnancy. We found that the group given the higher doses of L-phenylalanine had significantly more heart defects than the group given the lower dose and the controls. Ventricular septal defect was found in 80 % of the fetuses with congenital deformities of the heart. [¹⁴C] Leucine uptake by the embryos was significantly lower in the group loaded with L-phenylalanine than in the controls.
The activity of thymidine kinase, one of the rate-limiting enzymes in DNA synthesis, was significantly lower in the brain and heart tissues of the young rats loaded with L-phenylalanine than in the controls.
Thus, when blood levels of phenylalanine are high in early pregnancy, an amino acid imbalance in the embryo occurs during fetal organogenesis. Also, thymidine kinase decreases, which may hinder DNA synthesis. Both of these mechanisms seem to be involved in the higher incidence of fetal heart malformations in maternal phenylketonuria.     

Effect of nicotine on the development of fetal and suckling rats.

Nicotine, administered at a dose of 100 micrograms/kg/day from day 14 of gestation, did not affect maternal food intake, weight gain, length of gestation, litter size or fetal development; however, a daily dose of 1 mg/kg led to smaller litter size and higher incidence of stillbirth. Continued maternal administration of nicotine (100 micrograms/kg/day) until 12 days post partum did not affect newborn growth (body weight and length and size of heart and lung) during the first week after birth; during the second week, however, the nicotine-treated group lagged behind the controls. The stomachs of pups of nicotine-treated rats contained less food than those of controls; this difference increased with age, becoming more than 40% at 12 days. We suggest that lower milk production of nicotine-treated rats interferes with the normal development of the offspring during periods of rapid growth.     

Effects of oxytocin treatment in early life on body weight and corticosterone in adult offspring from ad libitum-fed and food-restricted rats

The aims of this study were: (1) to assess the effects of maternal undernutrition during pregnancy on adult offspring with regard to growth, body composition and plasma levels of glucose, insulin and corticosterone, and (2) to investigate whether oxytocin treatment early in life could ameliorate the adverse effects of food restriction in utero. Pups from ad libitum-fed and food-restricted (60% of ad libitum intake during pregnancy) rats were injected subcutaneously once a day with oxytocin or saline on days 1-14 after birth. At adult age (62 days), male offspring from food-restricted dams had lower body weight, less adipose tissue, lower plasma glucose but higher corticosterone levels, compared to offspring from ad libitum-fed dams. However, oxytocin-treated food-restricted males had higher body weight, higher glucose and lower corticosterone levels compared to their saline-treated counterparts. In conclusion, oxytocin treatment early in life seems to ameliorate some of the adverse effects of food restriction in utero.     

孕鼠叶酸缺乏对子鼠胰岛素样生长因子系统甲基化的影响

目的观察孕期叶酸缺乏对胎鼠生长发育及胰岛素样生长因子(IGF)系统甲基化的影响。方法将22只Sprague-Dawley雌鼠随机分为叶酸缺乏组(n=12)和正常对照组(n=10),分别喂养叶酸缺乏饲料和普通饲料,2周后与雄鼠交配,两组各8只雌鼠成功受孕,于怀孕第20天对孕鼠剖腹取胎,每组取32只胎鼠测量其头尾长、体重。两组分别另取8只胎鼠,采用ELISA法对其脑、肝脏组织中的叶酸、IGF-1、胰岛素样生长因子结合蛋白(IGFBP)-3水平进行检测。两组分别另取3只胎鼠,使用全基因组甲基化测序方法检测其脑、肝脏组织IGF系统的甲基化情况。同时采用ELISA法对两组孕鼠血清IGF-1、IGFBP-3水平进行检测。结果叶酸缺乏组胎鼠头尾长、体重较正常对照组降低(P0.05);叶酸缺乏组孕鼠血清IGF-1、IGFBP-3与胎鼠脑、肝脏组织中的叶酸、IGFBP-3水平均低于正常对照组(P0.05);叶酸缺乏组胎鼠脑组织中IGF-1R、IGF-2R、IGFBP-2、IGFBP-5、IGFBP-6、IGFBP-7的甲基化水平均高于正常对照组(P0.05);而在肝脏组织中,相比于正常对照组,叶酸缺乏组胎鼠IGF-1R、IGF-2R、IGFBP-3、IGFBP-5甲基化水平增加,IGF-2甲基化水平则下降(P0.05)。结论孕鼠叶酸缺乏会影响胎鼠宫内的生长发育,其机制可能与胰岛素生长因子系统的甲基化异常有关。