dinoprost and Abnormalities--Drug-Induced

Basic scientists and clinicians alike are in agreement that children of alcoholic mothers are at risk for a variety of birth defects. These defects have been labeled fetal alcohol syndrome or, in a milder form, fetal alcohol effects. Prevention or therapeutic intervention of this disorder requires an understanding of the mechanism of action of alcohol on the developing fetus. This paper addresses the possible role of prostaglandins as biochemical mediators of the teratogenic actions of alcohol.

Topics: Abnormalities, Drug-Induced; Animals; Aspirin; Brain; Chick Embryo; Cricetinae; Dinoprost; Embryonic and Fetal Development; Ethanol; Female; Fetal Alcohol Spectrum Disorders; Humans; Mice; Pregnancy; Prostaglandins; Prostaglandins E; Prostaglandins F; Rabbits; Rats

Intrauterine exposure to ethanol causes embryonic and fetal growth retardation and maldevelopment. Oxidative stress in mother and offspring has been suggested to be part of the teratogenic mechanism, and supplementation of antioxidative agents to the pregnant women may therefore be of value in future prophylactic treatment regimen. There is a need for in vivo experimental work in this field, and in the present study, our aim was to investigate whether chronic ethanol consumption induced congenital malformations in rats and, if so, whether dietary supplementation of vitamin E (alpha-tocopherol) diminished such maldevelopment.. Female Sprague-Dawley rats were given drinking water containing 20% ethanol and half of these received food containing 5% vitamin E. Non-ethanol-exposed female rats, with or without vitamin E treatment, served as controls. The pregnancy was interrupted on gestational day 20 when the offspring was evaluated morphologically and fetal hepatic 8-iso-PGF(2alpha) levels were measured to assess the degree of fetal oxidative stress.. Exposure to 20% ethanol increased maternal blood ethanol to 1.5 promille and increased resorption and malformation rates in the offspring. Maternal vitamin E treatment did not affect blood ethanol levels, but normalized fetal development. The fetal hepatic levels of 8-iso-PGF(2alpha) were increased in the ethanol-exposed group and normalized by vitamin E treatment of the mother.. Ethanol exposure disturbs embryogenesis partly by enhanced oxidative stress, and the adverse effects can be ameliorated by antioxidative treatment.

Topics: Abnormalities, Drug-Induced; alpha-Tocopherol; Animals; Antioxidants; Central Nervous System Depressants; Dinoprost; Embryonic Development; Ethanol; Female; Fetal Growth Retardation; Lipid Peroxidation; Liver; Oxidative Stress; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley

Topics: Abnormalities, Drug-Induced; Animals; Culture Techniques; Dinoprost; Embryo, Mammalian; Embryonic Development; Exudates and Transudates; Fallopian Tube Diseases; Female; Lipid Peroxidation; Oxidative Stress; Rats; Reactive Oxygen Species; Teratogens; Yolk Sac

Previous experimental studies suggest that diabetic embryopathy is associated with an excess of radical oxygen species (ROS), as well as with a disturbance of prostaglandin (PG) metabolism. We aimed to investigate the relationship between these pathways and used hyperglycemia in vitro (embryo culture for 24-48 h) and maternal diabetes in vivo to affect embryonic development. Subsequently, we assessed lipid peroxidation and gene expression of cyclooxygenase (COX)-1 and -2 and measured the concentration of prostaglandin E2 (PGE2) in embryos and membranes. Both hyperglycemia in vitro and maternal diabetes in vivo caused embryonic dysmorphogenesis and increased embryonic levels of 8-epi-PGF2alpha, an indicator of lipid peroxidation. Addition of N-acetylcysteine (NAC) to the culture medium normalized the morphology and 8-epi-PGF2alpha concentration of the embryos exposed to high glucose. Neither hyperglycemia nor diabetes altered COX-1 expression, but embryonic COX-2 expression was diminished on gestational day 10. The PGE2 concentration of day 10 embryos and membranes was decreased after exposure to high glucose in vitro or diabetes in vivo. In vitro addition of NAC to high glucose cultures largely rectified morphology and restored PGE2 concentration, but without normalizing the COX-2 expression in embryos and membranes. Hyperglycemia/diabetes-induced downregulation of embryonic COX-2 gene expression may be a primary event in diabetic embryopathy, leading to lowered PGE2 levels and dysmorphogenesis. Antioxidant treatment does not prevent the decrease in COX-2 mRNA levels but restores PGE2 concentrations, suggesting that diabetes-induced oxidative stress aggravates the loss of COX-2 activity. This may explain in part the antiteratogenic effect of antioxidant treatment.

Topics: Abnormalities, Drug-Induced; Animals; Congenital Abnormalities; Cyclooxygenase 1; Cyclooxygenase 2; Diabetes Mellitus, Experimental; Dinoprost; Dinoprostone; Embryo, Mammalian; Embryonic and Fetal Development; F2-Isoprostanes; Female; Gene Expression; Indomethacin; Isoenzymes; Lipid Peroxides; Membrane Proteins; Pregnancy; Pregnancy Complications; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Abortion, Criminal; Abortion, Induced; Adolescent; Consanguinity; Dinoprost; Female; Humans; Infant, Newborn; Pregnancy; Pregnancy Trimester, First

Dibenzyloxyindanpropionic acid (DIPA) is an anti-abortifacient prostaglandin F2 alpha(PGF2 alpha) antagonist. Significant protection against PGF2 alpha-induced abortion in Charles River CD-1 mice is afforded by 50 mg/kg DIPA, administered i.m. twice daily from day-15 of gestation; two days prior to PGF2 alpha challenge. In the present teratological evaluation, CD-1 mice were treated either daily throughout gestation with 50 mg/kg DIPA i.m., or only on day-15 of gestation with two doses each of 50 or 200 mg/kg DIPA i.m. Controls received saline injections. Some dams were delivered by cesarian section on day-19 of gestation, while others were allowed to deliver spontaneously at term. Parameters monitored in the offspring were litter sizes, body weights, sex ratios, viability of progeny, external malformations, cleft palate, skeletal anomalies, patency (prenatal) and closure (postnatal) of the ductus arteriosus, gross anatomy of organs, and histopathological examination of tissues. Consistent with a PGF2 alpha antagonistic mechanism of action, DIPA treatment throughout gestation prolonged pregnancy to the upper normal limit. Prenatal administration of DIPA increased the pseudopregnancy rate, but none of the treatment schedules produced any recognizable teratogenic effects.

Topics: Abnormalities, Drug-Induced; Abortifacient Agents; Animals; Dinoprost; Drug Evaluation, Preclinical; Female; Mice; Pregnancy; Prostaglandins F; Quaternary Ammonium Compounds