ArticleProceedings of the National Academy of Sciences of the United States of America2012
A paradoxical teratogenic mechanism for retinoic acid.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 83 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
83 citing papers in PubMed, 1 synthesis or guideline pooled it, 139 citations in OpenAlex.
- The Relationship between Maternal Nutrition during Pregnancy and Offspring Kidney Structure and Function in Humans: A Systematic Review.Nutrients · 2018Pooled it
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- Vitamin A5: Evidence, Definitions, Gaps, and Future Directions.Nutrients · 2025Review
- Feedback regulation of retinaldehyde reductase DHRS3, a critical determinant of retinoic acid homeostasis.FEBS letters · 2025Article
- Review
- The genetics and pathogenesis of CAKUT.Nature reviews. Nephrology · 2023Review
- Human nutritional relevance and suggested nutritional guidelines for vitamin A5/X and provitamin A5/X.Nutrition & metabolism · 2023Review
- Trails to Research: an Inquiry-Based Course Using Zebrafish To Provide Research Experience to Tribal College Students.Journal of microbiology & biology education · 2023Article
- Genetically programmed retinoic acid deficiency during gastrulation phenocopies most known developmental defects due to acute prenatal alcohol exposure in FASD.Frontiers in cell and developmental biology · 2023Article
- ALDH1A2-related disorder: A new genetic syndrome due to alteration of the retinoic acid pathway.American journal of medical genetics. Part A · 2023Article
- Hyperglycemia alters retinoic acid catabolism in embryos exposed to a maternal diabetic milieu.PloS one · 2023Article
- A quest for genetic causes underlying signaling pathways associated with neural tube defects.Frontiers in pediatrics · 2023Review
- Retinoid metabolism: new insights.Journal of molecular endocrinology · 2022Review
- The term CAKUT has outlived its usefulness: the case for the prosecution.Pediatric nephrology (Berlin, Germany) · 2022Review
- The Prevalence and Clinical Significance of Congenital Anomalies of the Kidney and Urinary Tract in Preterm Infants.JAMA network open · 2022Article
- Disease mechanisms of monogenic congenital anomalies of the kidney and urinary tract American Journal of Medical Genetics Part C.American journal of medical genetics. Part C, Seminars in medical genetics · 2022Review
- Administration of retinoic acid to pregnant mice increases the number of fetal mouse glomeruli.Biochemistry and biophysics reports · 2022Article
- Review
- Article
23 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Retinoic acid, an active metabolite of vitamin A, plays essential signaling roles in mammalian embryogenesis. Nevertheless, it has long been recognized that overexposure to vitamin A or retinoic acid causes widespread teratogenesis in rodents as well as humans. Although it has a short half-life, exposure to high levels of retinoic acid can disrupt development of yet-to-be formed organs, including the metanephros, the embryonic organ which normally differentiates into the mature kidney. Paradoxically, it is known that either an excess or a deficiency of retinoic acid results in similar malformations in some organs, including the mammalian kidney. Accordingly, we hypothesized that excess retinoic acid is teratogenic by inducing a longer lasting, local retinoic acid deficiency. This idea was tested in an established in vivo mouse model in which exposure to excess retinoic acid well before metanephric rudiments exist leads to failure of kidney formation several days later. Results showed that teratogen exposure was followed by decreased levels of Raldh transcripts encoding retinoic acid-synthesizing enzymes and increased levels of Cyp26a1 and Cyp26b1 mRNAs encoding enzymes that catabolize retinoic acid. Concomitantly, there was significant reduction in retinoic acid levels in whole embryos and kidney rudiments. Restoration of retinoic acid levels by maternal supplementation with low doses of retinoic acid following the teratogenic insult rescued metanephric kidney development and abrogated several extrarenal developmental defects. This previously undescribed and unsuspected mechanism provides insight into the molecular pathway of retinoic acid-induced teratogenesis.
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