6‐mercaptopurine‐induced alterations in mineral metabolism and teratogenesis in the rat

Amemiya, Kenjie; Keen, Carl L.; Hurley, Lucille S.

doi:10.1002/tera.1420340312

Cited by 33 publications

(5 citation statements)

References 17 publications

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“…While the concept that APR-induced changes in maternal-fetal zinc metabolism might represent a common mechanism contributing to the teratogenicity of a wide variety of toxicants and environmental insults has received considerable support, it still must be viewed as a hypothesis. Regardless, it is exciting to consider the possibility that this concept could help to explain the observation that the teratogenicity of diverse agents ranging from thalidomide (Jackson and Schumacher, 1979), acetazolamide (Hackman and Hurley, 1983), alcohol (Carey et al, 2003b;Miller et al, 1983), salicylate (Hackman and Hurley, 1984), and 6-MP (Amemiya et al, 1986) to alpha-hederin Duffy et al, 1997), can be modulated by the mother's intake of dietary zinc. From a larger perspective, this might provide one explanation for why women who consume ''poor diets'' have an elevated risk for pregnancy complications, as it would suggest that such women would have an increased sensitivity to teratogenic insults that trigger an APR.…”

Section: Secondary Deficiencies Of Zincmentioning

confidence: 97%

Zinc and reproduction: effects of zinc deficiency on prenatal and early postnatal development

Uriu‐Adams

Keen

2010

Birth Defects Research Pt B

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118

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A large body of evidence supports the concept that human pregnancy outcome is significantly influenced by the nutritional status of the mother. The consumption of "poor diets" has been associated with an increased risk for pregnancy complications, including gross structural birth defects, prematurity, low birth weight, and an increased risk for neurobehavioral and immunological abnormalities after birth. Forty-four years ago, zinc deficiency in mammals was shown to be teratogenic. Maternal zinc deficiency produces effects ranging from infertility and embryo/fetal death, to intrauterine growth retardation and teratogenesis. Postnatal complications of maternal zinc deficiency can also occur, and include behavioral abnormalities, impaired immunocompetence, and an elevated risk for high blood pressure in the offspring. It has been suggested that developmental zinc deficiency in humans can present a significant challenge to the conceptus, increasing the risk for numerous defects. Developmental zinc deficiency can occur through multiple pathways, and the concept that acute phase response-induced changes in maternal zinc metabolism may be a common cause of embryonic and fetal zinc deficiency is presented. Potential mechanisms underlying the teratogenic effects of zinc deficiency are reviewed. The potential value of maternal zinc supplementation in high risk pregnancies is discussed.

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Section: Secondary Deficiencies Of Zincmentioning

confidence: 97%

Zinc and reproduction: effects of zinc deficiency on prenatal and early postnatal development

Uriu‐Adams

Keen

2010

Birth Defects Research Pt B

Self Cite

118

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“…The 6-mercaptopurine (6-MP), anti-leukemic drug, is an immunosuppressive drug. The 6-MP has been shown to induce embryo-toxic effects, including a reduction in the number of implantation sites and also to have teratogenicity, which includes limb defects, micrognathia, and ventral hernia in rats (Amemiya et al, 1986;Furukawa et al, 2008). Furthermore, Bragonier et al (1964) suggested that placental tissues may be more sensitive to 6-MP than the fetus.…”

Section: Introductionmentioning

confidence: 99%

6-Mercaptopurine-induced histopathological changes and xanthine oxidase expression in rat placenta

et al. 2012

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The placenta secures the embryo and fetus to the endometrium and releases a variety of steroid and peptide hormones that convert the physiology of a female to that of a pregnant female. Chemical-induced alteration or deviation of placental function in the maternal and extraembryonic tissue can ultimately lead to pregnancy loss, congenital malformation and fetal death. The 6-mercaptopurine (6-MP), an anti-leukemic drug, is known to produce undesired effects on some organs, then the placenta/embryo toxicity of 6-MP was investigated in pregnant rats given 60 mg/kg with two intraperitoneal injections on gestation days (GD) 11 and 12. The rats were sacrificed and their placentas were collected on GD13 or 15. On GD15 small and limb-defected embryos were found in the 6-MP-treated rats. Placental weights were significantly reduced on GD15, as well as a reduced number of cells was detected in the labyrinth zone with both the labyrinth and basal zones having thinned. Cleaved caspase-3-positive cells increased in number in the labyrinth zone, while in the basal zone, glycogen cells reduced with cytolysis. The number of spongiotrophoblasts and trophoblastic giant cells also increased by 6-MP treatment. The 6-MP-treatment resulted in the increased xanthine oxidase (Xdh) expression in the placenta, which gene is related to the ischemic condition of tissues. These data suggest that apoptosis of the labyrinth zone cells may lead to decreased materno-fetal exchange. Moreover, subsequent ischemia in the placental tissue may occur and induce Xdh expression.

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“…6-MP induces embryo-toxic effects, including a reduction in the number of implantation sites and is also known as a teratogen, inducing limb defects, micrognathia, ventral hernia, skeletal, urogenital, central nervous system and ocular anomalies, cleft palate, diaphragmatic hernia, etc. in rats, mice and rabbits [1,2,13,18,19]. On the other hand, Bargnoier et al suggested that placental tissues may be more sensitive to 6-MP than the fetus, and it is known that the placentas from 6-MP-treated rats show a disproportionate reduction in thickness of the labyrinth zone with fibrinous degeneration of trophoblasts [3,24].…”

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confidence: 99%

Effect of 6-Mercaptopurine on Rat Placenta

et al. 2008

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ABSTRACT. In order to investigate the toxic effects of 6-mercaptopurine (6-MP) on placental development, we examined sequential morphology in the placentas from rats exposed to 6-MP. 6-MP was intraperitoneally administered at 60 mg/kg during gestation days (GDs) 11 to 12, and the placentas were sampled on GD 13, 15 or 21. In the 6-MP-treated group, maternal body weight suppression, increased death embryo/fetus ratio and some malformations were observed. The placenta weights were decreased on GDs 15 and 21. Macroscopically, placentas on GD 21 were small, brittle and thin with a white peripheral rim. Histopathologically, in the labyrinth zone, 6-MP treatment mainly evoked decreased mitosis on GDs 13 and 15, increased apoptotic cell on GDs 13, 15 and 21 and thinning on GDs 15 and 21. In the basal zone, 6-MP evoked decreased mitosis on GDs 13, and PAS-positive material in the spongiotrophoblasts was still detected on GD 15. Thickening of the basal zone was observed with cytolysis of glycogen cells, apoptosis and an increased number of composed cells on GD 21. In conclusion, 6-MP administration in pregnant rats induced growth arrest of the labyrinth zone and developmental delay in the basal zone, leading to small placentas. The fetotoxicity of 6-MP may be responsible for its direct anti-proliferative effects and resulting placental dysfunction.

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6‐mercaptopurine‐induced alterations in mineral metabolism and teratogenesis in the rat

Cited by 33 publications

References 17 publications

Zinc and reproduction: effects of zinc deficiency on prenatal and early postnatal development

Zinc and reproduction: effects of zinc deficiency on prenatal and early postnatal development

6-Mercaptopurine-induced histopathological changes and xanthine oxidase expression in rat placenta

Effect of 6-Mercaptopurine on Rat Placenta

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