Neonatal mouse hip joint and hindlimb anomalies induced by prenatal exposure to Ara-C

Chiba, Kazuaki; Ishikawa, Hitoshi; Rahman, Mohammed E.; Endo, Akira

doi:10.1016/0890-6238(96)00024-x

Cited by 4 publications

(3 citation statements)

References 16 publications

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“…Then total RNA was extracted using Isogen (Nippon Gene Co. Ltd., Toyama, Japan). The reverse transcriptase reaction for synthesis of the first strand cDNA was carried out with 15 g of sample in 60 l of reaction mixture using oligo(dT) [12][13][14][15][16][17][18] primer and a SUPERSCRIPT Preamplification System (Invitrogen, Carlsbad, CA). PCR was performed with pairs of oligonucleotide primers corresponding to the cDNA sequences of the rat mRNA (Table 1).…”

Section: Rna Extraction and Semiquantitative Rt-pcrmentioning

confidence: 99%

“…Ara-C is used in the clinical treatment for myelogenous leukemia and is associated with fetal growth restrictions and malformations such as microtis, auditory canal atresia, digit anomalies, and lower limb defects in humans [22][23][24]. It has a teratogenic effect and causes fetal growth retardation also in experimental animals [13,25,26]. Previously, we demonstrated that the administration of Ara-C to pregnant rats caused significant decreases of placental weight and thickness of the labyrinth zone with a marked increase in the number of apoptotic cells among trophoblastic cells of the placental labyrinth zone and confirmed that fetal weight was also restricted at 48 h after the administration [27].…”

Section: Introductionmentioning

confidence: 98%

“…Embryos and fetuses are vulnerable to genotoxic stress such as DNA damaging agents or radiation, and congenital anomalies are easily induced [13][14][15][16]. Genotoxic stress induces apoptosis and cell-cycle arrest in fetal tissues in a p53-dependent way, and this is recognized as a cause of congenital anomalies [15,[17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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Involvement of p53 in 1-β-d-Arabinofuranosylcytosine-Induced Trophoblastic Cell Apoptosis and Impaired Proliferation in Rat Placenta

Yamauchi

Katayama

Ueno

et al. 2004

Biology of Reproduction

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1-beta-D-Arabinofuranosylcytosine (Ara-C), a DNA-damaging agent, severely inhibits fetal growth and has teratogenicity. Recently, we reported that Ara-C also causes placental growth retardation and increases placental apoptosis. The aim of the present study is to elucidate the mechanisms of placental injury induced by genotoxic stress and involvement of p53, which mediates apoptosis and cell-cycle arrest after DNA damage. We injected Ara-C into pregnant rats on Day 13 of gestation and examined the placentas from 1 to 48 h after the administration. Terminal deoxynucleotidyltransferase-mediated dUTP end-labeling (TUNEL) revealed that the apoptosis of trophoblastic cells in the placental labyrinth zone increased from 3 h after the treatment and peaked at 6 h before returning to control levels at 48 h. An increase in cleaved caspase-3 immunoreactivity was also detected at 6 h. Proliferative activity as measured by immunohistochemistry for topoisomerase II alpha and by mitotic index significantly decreased after the treatment in the labyrinth zone. Immunoreactivity for p53 protein in the placental labyrinth zone was remarkably enhanced and peaked at 3 h after treatment, although no increase in p53 mRNA expression was detected with a reverse transcription- polymerase chain reaction. Regarding p53 target genes, p21, cyclinG1, and fas mRNA levels increased significantly and peaked at around 9 h after the treatment. These results indicate that Ara-C would induce apoptosis and impair cell proliferation in the placental labyrinth zone, and p53 and its transcriptional target genes may play an important role in the pathogenesis of the Ara-C-induced placental toxicity.

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Section: Rna Extraction and Semiquantitative Rt-pcrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

Involvement of p53 in 1-β-d-Arabinofuranosylcytosine-Induced Trophoblastic Cell Apoptosis and Impaired Proliferation in Rat Placenta

Yamauchi

Katayama

Ueno

et al. 2004

Biology of Reproduction

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Alpha-lipoic acid ameliorates cytarabine-induced developmental anomalies in rat fetus

Namoju

Chilaka

2020

Hum Exp Toxicol

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Cytarabine (Ara-C) is a nucleoside analogue used in the treatment of cancers and viral infections. It has teratogenic potential and causes a variety of birth defects in fetuses. Alpha-lipoic acid (ALA) is a natural antioxidant offers protection against the developmental toxicity induced by drug- or toxicant-exposure or pathological conditions. This study was aimed at evaluating the protective effect of ALA against Ara-C induced developmental toxicity in rat fetus. Pregnant rats divided into five groups and received normal saline, ALA200 mg/kg, Ara-C12.5 mg/kg, Ara-C25 mg/kg and, Ara-C25 mg/kg plus ALA200 mg/kg respectively from gestational day (GD) 8 to GD14 and sacrificed on GD21. Ara-C treatment led to a significant and dose-dependent decrease in food intake, weight gain, placental weight, and an increase in oxidative stress in pregnant rats. Further, the in-utero exposure to Ara-C led to an increase in fetal mortality, resorptions, oxidative stress, external morphological anomalies and limb abnormalities, and impaired ossification. Co-administration of ALA resulted in amelioration of the footprints of Ara-C induced toxicity in pregnant rats as well as the fetus. These findings indicate that the ALA supplementation offers protection against developmental toxicity caused by Ara-C prenatal exposure in rats.

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1-.BETA.-D-Arabinofuranosylcytosine (Ara-C)-induced Apoptosis in the Rat Fetal Tissues and Placenta

et al. 2003

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1-β-D-Arabinofuranosylcytosine (Ara-C), a cytidine analogue, inhibits DNA synthesis and is used for the treatment of myelogenous leukemia. On the other hand, it is also known that Ara-C has a teratogenic effect. In the present study, pregnant rats were treated with 250 mg/kg of Ara-C on day 13 of gestation, and fetal tissues and placentae were collected from 3 to 48 hours after treatment to examine the sequential histopathological changes induced by prenatal Ara-C treatment. The weights of fetuses and placentae and the thickness of the placental labyrinth zone were significantly reduced at 48 hours after treatment. In the fetal tissues such as central nervous system and mesenchymes and in the placental labyrinth zone, the number of pyknotic cells stained positively by the TUNEL method increased markedly after treatment with Ara-C. In most fetal tissues, the number began to increase from 3 to 6 hours and peaked at 9 to 12 hours after treatment. In the placental labyrinth zone, the number peaked at 6 hours after treatment. Electron microscopical features of the pyknotic cells consisted with the ultrastructural characteristics of apoptotic cells. In various fetal organs and placentae, abnormal induction of apoptosis is suggested to induce growth inhibition and have a certain relation to the malformations. Moreover, abnormal induction of apoptosis would have a deep connection with the cytotoxic effect of Ara-C which may affect proliferative cells in fetuses and placentae developing rapidly. (J Toxicol Pathol 2003; 16: 223-229)

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Neonatal mouse hip joint and hindlimb anomalies induced by prenatal exposure to Ara-C

Cited by 4 publications

References 16 publications

Involvement of p53 in 1-β-d-Arabinofuranosylcytosine-Induced Trophoblastic Cell Apoptosis and Impaired Proliferation in Rat Placenta

Involvement of p53 in 1-β-d-Arabinofuranosylcytosine-Induced Trophoblastic Cell Apoptosis and Impaired Proliferation in Rat Placenta

Alpha-lipoic acid ameliorates cytarabine-induced developmental anomalies in rat fetus

1-.BETA.-D-Arabinofuranosylcytosine (Ara-C)-induced Apoptosis in the Rat Fetal Tissues and Placenta

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