All-Trans-Retinoic Acid in Maternal Plasma and Teratogenicity in Rats and Rabbits

Tembe, E. A.; Honeywell, R.; Buss, Neil; Renwick, A.G.

doi:10.1006/taap.1996.0312

Cited by 23 publications

(11 citation statements)

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“…Serum concentrations of a number of teratogenic retinoids are raised above endogenous levels. In vivo studies (Buss et al, 1994; Tembe et al, 1996; Ritchie et al, 1998) have concluded, however, that the maternal serum concentrations of only one metabolite e.g., tRA, may not appropriately predict teratogenic risk. The finding that, if present in certain combinations, RP metabolites can induce malformations even when present below threshold concentrations can assist in assessing the teratogenic potential of a large oral dose of vitamin A.…”

Section: Discussionmentioning

confidence: 99%

Effect of co‐administration of retinoids on rat embryo development in vitro

Ritchie

Brown‐Woodman

Korabelnikoff

2003

Birth Defects Research

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Section: Discussionmentioning

confidence: 99%

Effect of co‐administration of retinoids on rat embryo development in vitro

Ritchie

Brown‐Woodman

Korabelnikoff

2003

Birth Defects Research

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“…A common characteristic of all-trans-RA pharmacokinetics in rats, rabbits, cynomolgus monkeys, and humans is the diminution of plasma drug concentrations after repeated dosing with this retinoid, although the extent and the time course of this phenomenon vary among species [90,102,198,199,[205][206][207][208]. In one of the studies performed with pregnant animals, the pharmacokinetics of retinoids in maternal plasma and whole embryos of pregnant rats and rabbits were compared following either a single oral dose of 6 mg all-trans-RA/kg body wt on GD 12 or the last of six daily doses of 6 mg all-trans-RA/kg from GD 7 to 12 [198].…”

Section: Rolementioning

confidence: 99%

The Role of Metabolism and Toxicokinetics in Retinoid Teratogenesis

Tzimas

Nau²

2001

CPD

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Retinoids (vitamin A and its analogs) exert profound effects on a wide variety of life processes, including morphogenesis and embryonic development. Several retinoids are also effective drugs for therapy of skin diseases and some types of cancer. However, the applicability of this class of compounds is limited by their teratogenic activity. A major question in retinoid toxicology has been the marked interspecies differences in the lowest teratogenic doses of 13-cis-retinoic acid and retinol. In addition, great attention has been drawn to the risk assessment of embryotoxicity resulting from excessive intake of vitamin A by pregnant women. The present review first gives an overview of the biochemistry, metabolism and mode of action of retinoids as well as their role in embryonic development. It then summarizes the results of recent studies on retinoid metabolism, toxicokinetics, and embryonic exposure and discusses how the available information provides explanation of the aforementioned interspecies variations. Finally, it presents some approaches for risk assessment of high vitamin A intake by humans based on various animal models and epidemiological studies.

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“…RA is necessary for early fetal cardiogenesis. Supplementing with excess vitamin A or RA during the gestational period leads to neonatal cardiac malformations [Tembe et al, 1996;Collins and Mao, 1999].…”

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confidence: 99%

Regulation of dHAND protein expression by all‐trans retinoic acid through ET‐1/ETAR signaling in H9c2 cells

2006

J of Cellular Biochemistry

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dHAND is thought to be a cardiac-restricted transcription factor during embryonic development. Vertebrate heart development involves many transcription factors such as Nkx2.5, GATA, and tbx5. All-trans retinoic acid (AtRA), the oxidative metabolite of vitamin A, can regulate the expression of these factors to affect embryonic heart development. However, the action of atRA on the expression of dHAND is rarely reported. To clarify whether atRA regulate the dHAND expression, we exposed cultured H9c2 cells (rat embryonic cardiomyocytes) to atRA and detected the protein expression of dHAND by Western blot analysis. We observed atRA can regulate the dHAND expression in a dose- and time-dependent manner. AtRA also inhibited endothelin-1 (ET-1) expression in a time-dependent manner. Further studies revealed that pretreatment with 10 microM BQ-123, a selective endothelin-1 receptor (ETAR) antagonist, for 2 h can significantly counteract the inhibition of 5 microM atRA treatment for 2 h of dHAND mRNA and protein expression. Taken together, these results suggest that atRA regulates dHAND expression by ET-1/ETAR signal transduction pathway in H9c2 cells. The mechanism of ET-1/ETAR signaling in controlling the level of dHAND protein is to reduce the levels of dHAND mRNA. It is possible for atRA to exert its cardiac teratogenesis during vertebrate embryonic development in this way.

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All-Trans-Retinoic Acid in Maternal Plasma and Teratogenicity in Rats and Rabbits

Cited by 23 publications

References 0 publications

Effect of co‐administration of retinoids on rat embryo development in vitro

Effect of co‐administration of retinoids on rat embryo development in vitro

The Role of Metabolism and Toxicokinetics in Retinoid Teratogenesis

Regulation of dHAND protein expression by all‐trans retinoic acid through ET‐1/ETAR signaling in H9c2 cells

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