Background:Exposure to ethanol in utero leads to several brain development disorders including retinal abnormalities whose underlying cellular pathogenesis remains elusive.We have previously reported changes in electr...Background:Exposure to ethanol in utero leads to several brain development disorders including retinal abnormalities whose underlying cellular pathogenesis remains elusive.We have previously reported changes in electroretinogram recordings in moderate fetal alcohol exposure(MFAE)vervet monkeys.The goal of this study is to characterize the anatomical effects of moderate MFAE during the third trimester in the vervet monkey retina.Methods:Using immunohistochemistry and Western blots,we analyzed changes in the expression of cell-type specific proteins that may occur in the MFAE retina compared to the normal retina.We also compared the basic retinal anatomy across groups by examining retinal layering and thickness.Results:Our main result indicates that GFAP(a potent marker of astrocytes)immunoreactivity was increased in the MFAE retina indicating strong astrogliosis.There was no obvious change in the overall anatomy in the MFAE retina and no significant differences in the mean thickness of each retinal layer.Furthermore,no significant changes in the morphology of the photoreceptors,horizontal cells,bipolar cells,and amacrines cells was observed.Conclusions:These data indicate that astrogliosis is a consequence of prenatal alcohol exposure and might explain the reported changes in the electroretinographic responses.展开更多
Pregnant women are often complicated with diseases that require treatment with medication.Most drugs administered to pregnant women are off-label without the necessary dose,efficacy,and safety information.Knowledge co...Pregnant women are often complicated with diseases that require treatment with medication.Most drugs administered to pregnant women are off-label without the necessary dose,efficacy,and safety information.Knowledge concerning drug transfer across the placental barrier is essential for understanding fetal drug exposure and hence drug safety and efficacy to the fetus.Transporters expressed in the placenta,including adenosine triphosphate(ATP)-binding cassette efflux transporters and solute carrier uptake transporters,play important roles in determining drug transfer across the placental barrier,leading to fetal exposure to the drugs.In this review,we provide an update on placental drug transport,including in vitro cell/tissue,ex vivo human placenta perfusion,and in vivo animal studies that can be used to determine the expression and function of drug transporters in the placenta as well as placental drug transfer and fetal drug exposure.We also describe how the knowledge of placental drug transfer through passive diffusion or active transport can be combined with physiologically based pharmacokinetic modeling and simulation to predict systemic fetal drug exposure.Finally,we highlight knowledge gaps in studying placental drug transport and predicting fetal drug exposure and discuss future research directions to fill these gaps.展开更多
文摘Background:Exposure to ethanol in utero leads to several brain development disorders including retinal abnormalities whose underlying cellular pathogenesis remains elusive.We have previously reported changes in electroretinogram recordings in moderate fetal alcohol exposure(MFAE)vervet monkeys.The goal of this study is to characterize the anatomical effects of moderate MFAE during the third trimester in the vervet monkey retina.Methods:Using immunohistochemistry and Western blots,we analyzed changes in the expression of cell-type specific proteins that may occur in the MFAE retina compared to the normal retina.We also compared the basic retinal anatomy across groups by examining retinal layering and thickness.Results:Our main result indicates that GFAP(a potent marker of astrocytes)immunoreactivity was increased in the MFAE retina indicating strong astrogliosis.There was no obvious change in the overall anatomy in the MFAE retina and no significant differences in the mean thickness of each retinal layer.Furthermore,no significant changes in the morphology of the photoreceptors,horizontal cells,bipolar cells,and amacrines cells was observed.Conclusions:These data indicate that astrogliosis is a consequence of prenatal alcohol exposure and might explain the reported changes in the electroretinographic responses.
基金supported by the National Institute on Drug Abuse(Grant P01DA032507)the Eunice Kennedy Shriver National Institute of Child Health and Human Development(Grant R01HD102786)。
文摘Pregnant women are often complicated with diseases that require treatment with medication.Most drugs administered to pregnant women are off-label without the necessary dose,efficacy,and safety information.Knowledge concerning drug transfer across the placental barrier is essential for understanding fetal drug exposure and hence drug safety and efficacy to the fetus.Transporters expressed in the placenta,including adenosine triphosphate(ATP)-binding cassette efflux transporters and solute carrier uptake transporters,play important roles in determining drug transfer across the placental barrier,leading to fetal exposure to the drugs.In this review,we provide an update on placental drug transport,including in vitro cell/tissue,ex vivo human placenta perfusion,and in vivo animal studies that can be used to determine the expression and function of drug transporters in the placenta as well as placental drug transfer and fetal drug exposure.We also describe how the knowledge of placental drug transfer through passive diffusion or active transport can be combined with physiologically based pharmacokinetic modeling and simulation to predict systemic fetal drug exposure.Finally,we highlight knowledge gaps in studying placental drug transport and predicting fetal drug exposure and discuss future research directions to fill these gaps.
