sta-2 and Fetal-Growth-Retardation

Fetal growth retardation (FGR) is a critical problem in the neonatal period, because a substantial population of infants born with FGR go on to develop various developmental disorders. In the present study, we produced FGR model rats by continuous administration of a synthetic thromboxane A2 analogue (STA2) to pregnant rats. The FGR pups exhibited a significant delay in postnatal neurological development. Moreover, behavioral analyses revealed the presence of a learning disability in juvenile FGR male rats. To investigate the mechanism underlying the neurological disorders, histological and biochemical analyses of the brain of FGR rats were performed. The density of neurons in the cortical plate of an FGR brain was low compared with the brains of a similarly aged, healthy rat. Consistent with this finding, the density of TUNEL-positive cells was higher in the cortical plate of FGR brains. Western blot analyses showed that the levels of three brain-specific chondroitin sulfate proteoglycans (CSPGs), neurocan, phosphacan, and neuroglycan C, were all significantly reduced in the brain of neonatal FGR rats compared with those of the control. The reduction of CSPG-levels and morphological changes in the brain may be relevant to neurological dysfunction in FGR.

Topics: Animals; Animals, Newborn; Brain; Cell Count; Cerebral Cortex; Chondroitin Sulfate Proteoglycans; Developmental Disabilities; Disease Models, Animal; Female; Fetal Growth Retardation; Growth Inhibitors; Humans; Infant, Newborn; Learning Disabilities; Male; Membrane Proteins; Neurocan; Pregnancy; Proteoglycans; Rats; Rats, Sprague-Dawley; Receptor-Like Protein Tyrosine Phosphatases, Class 5; Thromboxane A2

Intrauterine growth retardation (IUGR) is an important cause of prenatal and neonatal morbidity, and neurologic abnormalities. Although several animal models of IUGR have been developed for scientific investigation, few models approximate the pathophysiology in human fetal growth failure resulting from pregnancy-induced hypertension and preeclampsia. We developed an animal model of IUGR in which fetal growth restriction was induced by administering a synthetic thromboxane A(2) analogue (STA(2)) to the mother.. Timed pregnant Sprague-Dawley rats were used in this study. STA(2) was delivered into the peritoneal cavity of the pregnant female at a rate of 20 ng/h from day 13 of pregnancy. The effectiveness of this model was evaluated by monitoring the overall growth of the fetuses and neonates and measuring the weight and biochemical composition of individual organs.. Fetuses and neonates from the STA(2) group showed a highly significant weight reduction throughout the observation period from day 19 of gestation to postnatal day 7. Weight reduction near and at term exceeded 10% and became more pronounced during the first week after birth. Fetuses on the 20th gestational day exhibited a pattern of growth retardation characteristic of asymmetrical IUGR in which the weight reduction was prominent in the liver with relative sparing of the brain. However, the decrease in brain weight was more than 10%. The protein, DNA, and RNA contents of the liver were lower in the STA(2) group. The protein content of the forebrain and brainstem also decreased significantly in the STA(2) group compared with the control; however, the DNA content of the forebrain was higher in the STA(2) group.. This animal model may mimic human IUGR more closely than previous models because the growth restriction is induced in a truly chronic manner.

Topics: Animals; Disease Models, Animal; Female; Fetal Development; Fetal Growth Retardation; Infusions, Parenteral; Pregnancy; Rats; Rats, Sprague-Dawley; Thromboxane A2

IUGR was induced by maternal administration of synthetic thromboxane A2 (STA2) from the 13th day of gestation. Fetuses and neonates showed a markedly significant weight reduction. In E16 IUGR brain, no pathological abnormalities were found, but morphological changes appeared in the cortical plate of E18 IUGR brain. In E20 IUGR brain, ectopic clusters of differentiating cells cytologically mimicking neuroblasts were found in the neuroepithelial layer, but these abnormal clusters of cells in IUGR brain of late gestation were never observed in PN7. Morphometric analysis of coronal-sectional areas of the brain and cortical plate demonstrated that there were no differences between IUGR rats and controls in E16 and E18. These areas were, however, significantly reduced in E20 and PN7 growth-retarded rats compared with the control. Because the period of STA2 administration coincides with the neuro-developmental stage of cell migration and differentiation, reduction of the uteroplacental blood supply might cause a transient abnormal cytoarchitecture of the cerebral cortex resulting in brain growth retardation.

Topics: Animals; Animals, Newborn; Body Weight; Brain; Brain Diseases; Disease Models, Animal; Embryonic and Fetal Development; Female; Fetal Growth Retardation; Pregnancy; Rats; Rats, Sprague-Dawley; Thromboxane A2