A developmental toxicity study of tretinoin administered topically and orally to pregnant Wistar rats

Seegmiller, Robert E.; Ford, William H.; Carter, Melvin W.; Mitala, Joseph

doi:10.1016/s0190-9622(97)70061-6

Cited by 22 publications

(13 citation statements)

References 12 publications

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“…The downregulation of Vangl1/2 in spinal region from E15.5 to E19.5 was remarkable, while they slightly decreased on cranial region from E15.5 to E19.5 compared with control group (all PB0.01). Seegmiller et al, 1997), which was proven in our study as well.…”

Section: Discussionsupporting

confidence: 85%

Effects of Retinoic Acid on the Expressions ofVangl1andVangl2in Mouse Fetuses

Liu

Zhu

et al. 2008

Journal of Neurogenetics

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This study reports the effects of retinoic acid on the spatiotemporal expressions of Vangl1 and Vangl2 in mouse fetuses. A single dose of 120 mg/kg body weight of all-trans-retinoic acid suspended in olive oil was administered intragastrically to each pregnant BALB/C mice on embryonic day (E) 9.5 (group 1, G1) or E10.5 (group 2, G2); mice treated with pure olive oil on E9.5 or E10.5 served as control groups. The expression of Vangl1 and Vangl2 in fetuses was investigated by reverse transcriptase PCR (RT-PCR) and their spatial and temporal expression was detected by whole-mount in situ hybridization (WISH) on E10.5, E11.5, E13.5, E15.5, E17.5, and E19.5, respectively. The study indicated that the incidence of neural tube defects (NTDs) in live birth and craniofacial NTD rate were significantly higher in G1 (100% and 25.6%) than that in G2 (78.2% and 5.7%), both P < 0.01. Vangl1 and Vangl2 were strongly expressed throughout neurulation in embryos of control groups. G1 embryos exhibited a dramatic downregulation of Vangl1 and Vangl2 expression from cranial regions to posterior neuropore compared with the control group of G1 (all P < 0.01). In contrast, both transcripts in G2 embryos were significantly downregulated and weakly expressed in whole embryos on E11.5 and in the spinal region of the neural tube from E15.5 to E19.5, but moderately downregulated in the cranial region of the neural tube from E15.5 to E19.5 (all P < 0.01). In conclusion, Vangl1 and Vangl2 transcript downregulation might be implicated in the occurrence of mouse NTDs induced by retinoic acid.

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Section: Discussionsupporting

confidence: 85%

Effects of Retinoic Acid on the Expressions ofVangl1andVangl2in Mouse Fetuses

Liu

Zhu

et al. 2008

Journal of Neurogenetics

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“…Findings from animal developmental studies have shown that topically applied tretinoin causes an increase in skeletal variations, abortions, fetal death and cleft palate, and a decrease in fetal weight, some cases of which were dose related. [34][35][36][37][38][39][40] For instance, in one of these studies the maternal toxicity of topically applied tretinoin was severe enough to lead to a mortality rate of 20% in dams receiving a high dose. 37 Analysis of animal developmental toxicity studies suggests a lack of an embryofetal toxic effect.…”

Section: Discussionmentioning

confidence: 99%

“…[34][35][36][37][38][39][40] For instance, in one of these studies the maternal toxicity of topically applied tretinoin was severe enough to lead to a mortality rate of 20% in dams receiving a high dose. 37 Analysis of animal developmental toxicity studies suggests a lack of an embryofetal toxic effect. 41 Human data regarding possible fetal adverse effects of topical retinoids began to emerge as case reports in the late 1980s.…”

Section: Discussionmentioning

confidence: 99%

Pregnancy outcomes following first-trimester exposure to topical retinoids: a systematic review and meta-analysis

et al. 2015

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Evaluation of human data regarding the outcomes of topical-retinoid-exposed pregnancies is important in terms of counselling pregnant women with inadvertent exposure. The objective of this study was thus to determine whether exposure to topical retinoids leads to an increase in the risk of adverse pregnancy outcomes. We carried out a search using the Medline, Embase, Web of Science and Cochrane Central Register of Controlled Trials databases from inception to 4 December 2014. The selection, review and quality assessment of the studies were carried out by two independent reviewers according to predetermined inclusion criteria. Odds ratios (ORs) were calculated by the random effects method. This meta-analysis, including a total of 654 pregnant women who were exposed to topical retinoids, and 1375 unexposed control pregnant women, did not detect significant increases in rates of major congenital malformations [OR 1·22, 95% confidence interval (CI) 0·65-2·29], spontaneous abortions (OR 1·02, 95% CI 0·64-1·63), stillbirth (OR 2·06, 95% CI 0·43-9·86), elective termination of pregnancy (OR 1·89, 95% CI 0·52-6·80), low birthweight (OR 1·01, 95% CI, 0·31-3·27) or prematurity (OR 0·69, 95% CI 0·39-1·23). No significant heterogeneity was detected among the studies for the evaluated outcomes. The present meta-analysis ruled out a major increase in the rates of major congenital malformations, spontaneous abortions, low birthweight and prematurity. This result may be used primarily in reassuring women who were inadvertently exposed to topical retinoids during their pregnancy. However, the statistical power is not adequate to justify the use of topical retinoids during pregnancy.

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“…An earlier study in mice demonstrated that oral RA application at doses of 50 to 200 mg/ kg BW, administered at gestational days 8, 9, or 10, was associated with spina bifi da. In another case, oral retinoic acid administration at a dose of 10 mg/kg BW was associated with embryofetal alterations in Wistar rats (Seegmiller et al, 1997). In our histochemical study, a 10-mg/kg BW dose of RA at gestational days 8 through 10 had no teratogenic effects on NADPH-d-positive neurons of rat spinal cord at P1 or P21, although administration of an overdosage of RA during this time is conducive to malformations.…”

Section: Discussionmentioning

confidence: 46%

Postnatal Development of Spinal Cord and Liver Antioxidant Status in the Young of Retinol-Overdosed Female Rats

Patlevič

Vašková

Vaško

et al. 2013

Zeitschrift Für Naturforschung C

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The metabolic form of vitamin A, retinol, has a pivotal role in the nervous system development and neuronal differentiation, both during embryogenesis through maternal-fetal support and in the early postnatal life. Retinoic acid was administered orally at a dose of 10 mg/kg body weight to pregnant female rats through days 8 -10 of gestation. Spinal cord sections were processed for histochemical visualization one day after birth and on day 21, when weaning is expected. NADPH-diaphorase (NADPH-d)-positive neurons were found in the dorsal horn, around the central canal, and at the intermediolateral cell column on postnatal days 1 and 21 in both control and experimental groups. There were no NADPHd-positive structures in the ventral horn. The results suggest that prenatal administration of high doses of retinoic acid is not associated with postnatal morphological changes in NADPH-d-positive neurons in the rat spinal cord. Levels of antioxidants and related enzymes in retinoid storage organs were measured to estimate possible side effects. The activities of enzymes detoxifying superoxide radicals and peroxides were supressed after birth. A decrease in the level of reduced glutathione was observed on postnatal day 21, indicating an unbalanced redox environment.

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A developmental toxicity study of tretinoin administered topically and orally to pregnant Wistar rats

Cited by 22 publications

References 12 publications

Effects of Retinoic Acid on the Expressions ofVangl1andVangl2in Mouse Fetuses

Effects of Retinoic Acid on the Expressions ofVangl1andVangl2in Mouse Fetuses

Pregnancy outcomes following first-trimester exposure to topical retinoids: a systematic review and meta-analysis

Postnatal Development of Spinal Cord and Liver Antioxidant Status in the Young of Retinol-Overdosed Female Rats

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