Relationship Between Glucocorticoid And Its Pre-receptor Regulating Gene Polymorphism And Fetal Growth

Chapter Ⅰ: Relationship between late gestational serum cortisol and fetalgrowth in normal pregnancyObjective:To analyze the association between late gestational maternal and fetal serum cortisoland fetal birth weight and ultrasound parameters describing fetal growth done in early, middleand late pregnancy in normal pregnancy.Methods:Blood cortisol was quantified at delivery in432mother/child pairs who were normalpregnancy. Differential ultrasound examination of the fetal body was done in early, middle andlate pregnancy.Results: Ultrasound examination was done in early (gestational day89.95±7.31), middle(gestational day160.17±16.12) and late pregnancy (gestational day268.89±12.42). Thematernal cortisol was897.46±342.77nmol/L, the newborn's cortisol was229.67±139.04nmol/L and the ratio between maternal blood and newborn's blood was4.97±2.98. Bivariatecorrelation analyses showed that maternal cortisol shows a significantly negative correlation withthe following ultrasound parameters: late biparietal diameter (R~2=0.028, p=0.001), late headcircumference (R~2=0.045, p<0.001), late pectoral diameter (R~2=0.03, p=0.001), late abdominaldiameter (R~2=0.016, p=0.013), late abdominal circumference (R~2=0.025, p=0.002) and late femurlength (R~2=0.027, p=0.001). Multivariable regression analysis, considering timing of theultrasound examination, the child's sex, maternal BMI, maternal age, maternal body weight atdelivery, the timing of cortisol measurement and maternal uterine contractions states, revealedthat maternal serum cortisol was significantly negative correlated with ultrasound parametersdescribing the fetal brain: late biparietal diameter (R~2=0.512, p=0.009), late head circumference(R~2=0.498, p=0.001), middle biparietal diameter (R~2=0.819, p=0.013), middle cerebellum transverse diameter(R~2=0.76, p=0.014) and early biparietal diameter(R~2=0.819, p=0.013). Thesame analysis revealed that birth weight as well as other ultrasound parameters such asabdominal circumference and femur length were not correlated to maternal cortisol levels ornewborn's cortisol.Conclusions: Our study demonstrated that maternal cortisol secretion within physiologicalranges may be inversely correlated to fetal brain growth but not to birth weight. It remains to bedemonstrated weather maternal cortisol secretion negatively influencing fetal brain growthtranslates to adverse neurological outcomes in later life. Chapter Ⅱ:Relationship between ABCB1polymorphism and fetal growthand the cortisol transportation in maternofetal interfacePart Ⅰ: Relationship between ABCB1polymorphism and fetal growthObjective:To explore the relationship between ABCB1polymorphisms and fetal growth duringnormal pregnancy.Methods:The ABCB1/C3435T genotype was examined in262fetal and142maternal bloodsamples during normal pregnancy by polymerase chain reaction-restriction fragment lengthpolymorphism(PCR-RFLP). Fetal growth was assessed by differential ultrasound examinationof the fetal body prior to birth and by measuring birth weight.Results: The frequency of the gene polymorphisms of ABCB1/C3435T: In the fetal group, thefrequency of CC, CT, TT genotype were32.44%,53.82%,13.74%, respectively, and in thematernal group, were35.91%,50.70%,13.38%, respectively. There was no statistic differencebetween the two groups (P>0.05). All allele frequencies of the two research groups were foundto be in Hardy–Weinberg equilibrium(P>0.05).The maternal ABCB1/C3435T polymorphismshowed even no trend for an association with birth weight or any ultrasound parameterdescribing late gestational fetal body shape. Genotyping the newborns, however, demonstratedthat newborns carrying two copies of the T allele had a birth weight of3176.39g, whereas CTand CC newborns had a birth weight of3345.04g (p=0.022). Adjusting for gestational age atdelivery, child's sex, maternal BMI, maternal age and body weight at delivery confirmed thisfinding (p=0.009). Considering gestational day of late ultrasound examination, gestational ageat delivery, child's sex, maternal BMI, maternal age and maternal body weight at delivery, the fetal ABCB1/C3435T genotype revealed likewise a significant negative correlation withabdominal diameter and abdominal circumference (R~2=0.538, p=0.010and R~2=0.534, p=0.005,respectively).Conclusions: Low birth weight maybe a risk factor for cardiovascular diseases in later life. Thefetal ABCB1/C3435T gene polymorphism may contribute to this risk. Since P-glycoproteincontrols transport of various biological agents, we suggest that P-glycoprotein is involved in thetransport of biological agents to the fetus that are important for normal fetal growth. Part Ⅱ: Relationship between ABCB1polymorphism and the cortisoltransportation in maternofetal interfaceObjective: To explore the relationship between ABCB1polymorphisms and the cortisoltransportation in maternofetal interface during normal pregnancy.Methods: The ABCB1/C3435T genotype was examined with the same method part I. Bloodserum cortisol levels were measured with the same method as chapter I.Results: The fetal blood serum cortisol in the TT genotype group was significantly lower thanthose in the CT and CC+CT genotype groups(p<0.05); The blood serum maternal/fetal cortisolratio in the TT genotype group was significantly higher than those in the CT and CC+CTgenotype group (p<0.05). Multivariable regression analyses, considering gestational age at delivery,the child's sex, the timing of cortisol measurement and maternal uterine contractions states, showed thatthe fetal ABCB1/C3435T genotype revealed a significantly negative correlation with fetalblood serum cortisol (R~2=0.399,B=-33.47,p=0.003) and a positive correlation with blood serummaternal/fetal cortisol ratio (R~2=0.260,B=0.589,p=0.021).The maternal ABCB1/C3435Tpolymorphism assessed by comparable models showed no significant association with theblood serum cortisol level.Conclusions: The fetal ABCB1/C3435T polymorphism is related to the cortisol transportationin maternofetal interface during normal pregnancy. Chapter Ⅲ:Relationship between HSD11B2polymorphism and fetal growthand the cortisol metabolism in maternofetal interfaceObjective: To observe the relationship between HSD11B2polymorphism and the cortisolmetobolism in maternofetal interface and fetal growth during normal pregnancy.Methods: The first intron of HSD11B2(CA)nmicrosatellite polymorphism was at detected in187mother/child pairs during normal pregnancy by PCR-capillary electrophoresis. TheHSD11B2promoter/G-209A,G-194C,G-151A and G-126A genotype were examined in33Chinese han samples, which were randomly selected from the total study population, by genesequencing. Blood serum cortisol levels were measured with the same method as chapter I.Results: All of the HSD11B2promoter/G-209A,G-194C,G-151A and G-126A genotype wereGG, none of these sites were GC,CC,GA or AA in33Chinese han population. Multivariableregression analysis, considering gestational age at delivery, the child's sex, the timing of cortisolmeasurement and maternal uterine contractions states, showed that the fetal HSD11B2(CA)nmicrosatellite polymorphism(LL group VS SS+SL group) revealed a positive correlation withmaternal serum cortisol(R~2=0.26,B=96.27, p=0.007). Assessed by comparable models, none ofthe significant relationships between the fetal HSD11B2(CA)nmicrosatellite polymorphismand fetal serum cortisol, between maternal HSD11B2(CA)nmicrosatellite polymorphism andfetal or maternal serum cortisol, between maternal or fetal HSD11B2(CA)nmicrosatellitepolymorphism and any of the late pregnancy ultrasound measurements or birth weight werefounded.Conclusions: The fetal HSD11B2(CA)nmicrosatellite polymorphism is related to the cortisolmetabolism in maternofetal interface during normal pregnancy. Chapter Ⅳ: Relationship between late gestational serum cortisol andplacental stereology in normal pregnancyObjective: To analyze the association between late gestational maternal and fetal serum cortisoland placental stereology. Methods:30normal full-term pregnancy women, who were not in labor and their babies weredelivered by cesarean section, were randomly recruited in this study. A sterological study on theplacental villous capillary was evaluated with anti-CD34as the labelled vascular endothelialcells. The protein expressions of11β-HSD2and p-glycoprotein in the placenta were detected bywestern-blotting. Blood serum cortisol levels were measured with the same method as chapter I.Results: The maternal cortisol was631.227±176.75nmol/L, the newborn's cortisol was116.42±41.67nmol/L and the ratio between maternal blood and newborn's blood was6.29±3.59.Both of bivariatecorrelation analysis and multivariable regression analysis showed that the length density (Lv),the volume density (Vv) and the weight of the placental villous capillary in normal pregnancywere not significantly related to maternal or fetal serum cortisol or the protein expressions of11β-HSD2and p-glycoprotein in the placenta.Conclusions: The impact of maternal or fetal serum cortisol in normal full-term pregnancywithin physiological ranges on placental stereological parameters is not significant.