tretinoin and Premature-Birth

Per- and polyfluoroalkyl substances (PFAS) are a chemical class of highly stable, fluorinated compounds popular for use in a variety of consumer products. PFAS environmental persistence in drinking water contributes to acute exposure in humans and subsequent bioaccumulation of the compounds in the liver and lung tissue. Prenatal PFAS exposure has been associated with lowered birth weight, premature birth, and developmental defects including cranio-facial abnormalities. The cytochrome P450 enzyme CYP3A7 is responsible for facilitating a variety of reactions essential for proper fetal development in humans. In addition to drug metabolism, CYP3A7 is responsible for metabolizing endogenous ligands in the developing human liver, including the steroid precursor dehydroepiandrosterone 3-sulfate (DHEA-S), essential for estriol synthesis during pregnancy, along with the morphogen all-trans-retinoic acid (atRA). Interference with estriol synthesis during pregnancy, as well as atRA clearance, is known to result in similar effects associated with prenatal PFAS exposure including lowered birth weight, premature birth, and developmental defects. We hypothesized that PFAS compounds bind to the CYP3A7 enzyme resulting in its inhibition. We implemented a series of binding studies using spectral characterization of six PFAS compounds (PFOA, PFOS, GenX, PFNA, PFNS, and PFHxS), and evaluated their interactions with recombinant CYP3A7. In addition, we screened PFAS for their ability to inhibit CYP3A7 oxidative activity using dibenzylfluorescein, a fluorescent probe, and DHEA-S, an endogenous substrate of CYP3A7. Our data demonstrate that of the six PFAS tested, PFOA, PFOS, PFNA, and PFHxS bind to and inhibit CYP3A7.

Topics: Birth Weight; Cytochrome P-450 CYP3A; Dehydroepiandrosterone; Female; Fluorocarbons; Heme; Humans; Iron; Pregnancy; Premature Birth; Tretinoin; Water

Despite recent advances in perinatal medicine, bronchopulmonary dysplasia (BPD) remains the most common complication of preterm birth. Inflammation, the main cause for BPD, results in arrested alveolarization. All trans-retinoic acid (ATRA), the active metabolite of Vitamin A, facilitates recovery from hyperoxia induced cell damage. The mechanisms involved in this response, and the genes activated, however, are poorly understood. In this study, we investigated the mechanisms of action of ATRA in human lung epithelial cells exposed to hyperoxia. We hypothesized that ATRA reduces hyperoxia-induced inflammatory responses in A549 alveolar epithelial cells.. A549 cells were exposed to hyperoxia with or without treatment with ATRA, followed by RNA-seq analysis.. Transcriptomic analysis of A549 cells revealed ~2,000 differentially expressed genes with a higher than 2-fold change. Treatment of cells with ATRA alleviated some of the hyperoxia-induced changes, including Wnt signaling, cell adhesion and cytochrome P450 genes, partially through NF-κB signaling.. Our findings support the idea that ATRA supplementation may decrease hyperoxia-induced disruption of the neonatal respiratory epithelium and alleviate development of BPD.

Topics: Alveolar Epithelial Cells; Animals; Animals, Newborn; Bronchopulmonary Dysplasia; Female; Humans; Hyperoxia; Infant, Newborn; Lung; NF-kappa B; Pregnancy; Premature Birth; Tretinoin; Wnt Signaling Pathway

The authors undertook this study to assess the effect of preterm delivery with respect to neural protection in a congenital myelomeningocele (MMC) mouse model.. After confirmation of pregnancy in 15 female mice, a congenital MMC model was produced by administration of retinoic acid on the 7th day of gestation. The pregnant mice underwent cesarean sections on Days 15 (n = 5, Group E15), 17 (n = 5, Group E17), and 19 (n = 5, Group E19). Histological analyses were conducted on the lumbar defect and on the craniocervical junction in all fetuses with MMC.. Fetuses in Group E19 showed the most significant injury to neural tissue of the spinal cord at the MMC area followed by those in Group E17, with Group E15 being the least affected. All groups exhibited a degree of Chiari malformation; Group E19 was the most affected, followed by Group E17, and Group E15 was the least affected.. Development of both Chiari malformation and exposed spinal cord injury are progressive during gestation. Preterm delivery in this mouse model of congenital MMC may minimize the degree of injury to the spinal cord neural tissue and the degree of Chiari malformation.

Topics: Animals; Arnold-Chiari Malformation; Cesarean Section; Disease Models, Animal; Female; Gestational Age; Meningomyelocele; Mice; Pregnancy; Premature Birth; Spinal Cord; Time Factors; Tretinoin

Administration of retinoic acid (RA), the active metabolite of vitamin A, is linked to the stimulation of nephrogenesis. The aim of this study was to determine whether early postnatal administration of RA could enhance ongoing nephrogenesis in a baboon model of premature birth. Unbiased stereological methods were used to estimate kidney volume, renal corpuscle volume, and nephron number. The percentage of abnormal glomeruli and the number of glomerular generations was also determined in the kidneys of preterm control (n = 6) and preterm +RA (n = 6) animals that received 500 microg/kg/d of all-trans RA after premature delivery. There was no significant difference between the preterm control and the preterm +RA groups in kidney size, nephron number (preterm control: 329,924 +/- 41,752; preterm +RA: 354,041 +/- 52,095; p = 0.59), renal corpuscle volume, number of glomerular generations, or the percentage of abnormal glomeruli. The proportion of abnormal glomeruli did not appear to be linked to any elements of postnatal care examined. The results of this study indicate that early postnatal administration of RA is unable to stimulate nephrogenesis in the kidney of the preterm baboon. Encouragingly, it does not appear to have any adverse effects on kidney development.

Topics: Animals; Animals, Newborn; Birth Weight; Female; Gestational Age; Immunohistochemistry; In Situ Hybridization; Kidney; Kidney Glomerulus; Nephrons; Organ Size; Organogenesis; Papio; Platelet Endothelial Cell Adhesion Molecule-1; Podocytes; Pregnancy; Premature Birth; Tretinoin; Vascular Endothelial Growth Factor A; Vitamins; WT1 Proteins

Acute promyelocytic leukemia (APL) in pregnancy poses serious danger to both the mother and fetus. Cytotoxic chemotherapy may cause teratogenicity to the fetus. APL is unique because it is usually associated with a coagulopathy that markedly increases the risk for the mother and fetus. A 21 year old lady with APL in her third trimester of pregnancy was treated with oral tretinoin. Tretinoin reversed the coagulopathy and normalised her blood counts without causing cytotoxic damage associated with cancer chemotherapy. Fetal distress occurred at 37 weeks of gestation and an emergency caesarean section was performed without complications and no blood transfusion support was needed as her coagulopathy and thrombocytopenia had resolved. A remission was achieved with only tretinoin induction. She subsequently had consolidation and maintenance chemotherapy. The mother and baby remain well at 4 years from completion of chemotherapy. A total of 10 pregnancies associated with APL have been reported in the current literature. Premature delivery and a fetal arrhythmia were the only complications. Although retinoin is considered teratogenic, its use so far in second and third trimester has been safe.

Topics: Antineoplastic Agents; Disseminated Intravascular Coagulation; Female; Heart Rate, Fetal; Humans; Leukemia, Promyelocytic, Acute; Malaysia; Pregnancy; Pregnancy Complications; Pregnancy Trimester, Third; Premature Birth; Tretinoin; Young Adult