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Early ketamine exposure results in cardiac enlargement and heart dysfunction in Xenopus embryos.

Guo R, Liu G, Du M, Shi Y, Jiang P, Liu X, Liu L, Liu J, Xu Y - BMC Anesthesiol (2016)

Bottom Line: However, with the exception of studies about the nervous system, studies about the effect of early ketamine exposure on embryos are rare.Moreover, the heart rate and ventricular shortening fraction were decreased, findings indicative of heart dysfunction.The heart enlargement and decreased VSF may result from the down-regulation of XMLC2 mRNA and protein levels.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing, 400014, PR China.

ABSTRACT

Background: Ketamine is a commonly used clinical anesthetic and a popular recreational drug. However, with the exception of studies about the nervous system, studies about the effect of early ketamine exposure on embryos are rare. Xenopus laevis is a commonly used vertebrate model for assessing teratogenicity. Therefore, we treated Xenopus embryos with ketamine to evaluate its teratogenicity on embryos.

Methods: Xenopus embryos were treated with ketamine from stages 8 to 21. Embryonic and cardiac morphology were analyzed using living embryo imaging and whole-mount RNA in situ hybridization (WMISH). Heart function was measured by heart rate and ventricular shortening fraction (VSF). The mRNA expression levels of several heart development-related genes were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The protein expression levels of XMLC2, phospho-histone H3 (pH3) and histone H3 were determined by western blot.

Results: Ketamine caused concentration-dependent increases in mortality and shortening of body length. At a dose of 0.5 mg/ml, ketamine exposure resulted in cardiac enlargement as the primary manifestation of several malformations: gut defects, a curved axis and shortened body length. Cardiac cells underwent increased proliferation. Moreover, the heart rate and ventricular shortening fraction were decreased, findings indicative of heart dysfunction. XMLC2 expression levels were down-regulated at stages 28, 32/33, 35/36 and 46.

Conclusions: Ketamine exposure during early development has teratogenic effects on Xenopus embryos. The heart enlargement and decreased VSF may result from the down-regulation of XMLC2 mRNA and protein levels. These findings provide new insight into the potential fetal defects induced by ketamine exposure during early pregnancy.

No MeSH data available.


Related in: MedlinePlus

The effect of ketamine on embryos at stage 46. a Mortality rate of increasing concentrations of ketamine (0.1, 0.125, 0.25, 0.5, 1, 2, 5, 10, 25 mg/ml). b Malformations at three exposure concentrations of ketamine (0.125, 0.5, 2 mg/ml). Hearts are marked by white punctiform curves. The arrowhead indicates a curved axis. Scale bar = 100 μm. c Comparison of body lengths at three exposure concentrations. aP < 0.05 vs. control group; bP < 0.05 vs. 0.125 mg/ml ketamine-treated group; cP < 0.05 vs. 0.5 mg/ml ketamine-treated group. The data represent the means ± SD
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Fig1: The effect of ketamine on embryos at stage 46. a Mortality rate of increasing concentrations of ketamine (0.1, 0.125, 0.25, 0.5, 1, 2, 5, 10, 25 mg/ml). b Malformations at three exposure concentrations of ketamine (0.125, 0.5, 2 mg/ml). Hearts are marked by white punctiform curves. The arrowhead indicates a curved axis. Scale bar = 100 μm. c Comparison of body lengths at three exposure concentrations. aP < 0.05 vs. control group; bP < 0.05 vs. 0.125 mg/ml ketamine-treated group; cP < 0.05 vs. 0.5 mg/ml ketamine-treated group. The data represent the means ± SD

Mentions: Xenopus embryos were exposed to ketamine from stage 8 to stage 21. When the embryos developed to stage 46, we counted embryonic mortality within each ketamine-treated group. The result demonstrated that as the exposure concentration increased, the mortality rate also increased (Fig. 1a). Ketamine concentrations of 0.125, 0.5 and 2 mg/ml were chosen to observe the embryonic phenotype. It demonstrated that with increasing ketamine concentrations, body lengths gradually shortened (P < 0.05), hearts enlarged, and curved body axis was found at high concentrations (Fig. 1b-c).Fig. 1


Early ketamine exposure results in cardiac enlargement and heart dysfunction in Xenopus embryos.

Guo R, Liu G, Du M, Shi Y, Jiang P, Liu X, Liu L, Liu J, Xu Y - BMC Anesthesiol (2016)

The effect of ketamine on embryos at stage 46. a Mortality rate of increasing concentrations of ketamine (0.1, 0.125, 0.25, 0.5, 1, 2, 5, 10, 25 mg/ml). b Malformations at three exposure concentrations of ketamine (0.125, 0.5, 2 mg/ml). Hearts are marked by white punctiform curves. The arrowhead indicates a curved axis. Scale bar = 100 μm. c Comparison of body lengths at three exposure concentrations. aP < 0.05 vs. control group; bP < 0.05 vs. 0.125 mg/ml ketamine-treated group; cP < 0.05 vs. 0.5 mg/ml ketamine-treated group. The data represent the means ± SD
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4836076&req=5

Fig1: The effect of ketamine on embryos at stage 46. a Mortality rate of increasing concentrations of ketamine (0.1, 0.125, 0.25, 0.5, 1, 2, 5, 10, 25 mg/ml). b Malformations at three exposure concentrations of ketamine (0.125, 0.5, 2 mg/ml). Hearts are marked by white punctiform curves. The arrowhead indicates a curved axis. Scale bar = 100 μm. c Comparison of body lengths at three exposure concentrations. aP < 0.05 vs. control group; bP < 0.05 vs. 0.125 mg/ml ketamine-treated group; cP < 0.05 vs. 0.5 mg/ml ketamine-treated group. The data represent the means ± SD
Mentions: Xenopus embryos were exposed to ketamine from stage 8 to stage 21. When the embryos developed to stage 46, we counted embryonic mortality within each ketamine-treated group. The result demonstrated that as the exposure concentration increased, the mortality rate also increased (Fig. 1a). Ketamine concentrations of 0.125, 0.5 and 2 mg/ml were chosen to observe the embryonic phenotype. It demonstrated that with increasing ketamine concentrations, body lengths gradually shortened (P < 0.05), hearts enlarged, and curved body axis was found at high concentrations (Fig. 1b-c).Fig. 1

Bottom Line: However, with the exception of studies about the nervous system, studies about the effect of early ketamine exposure on embryos are rare.Moreover, the heart rate and ventricular shortening fraction were decreased, findings indicative of heart dysfunction.The heart enlargement and decreased VSF may result from the down-regulation of XMLC2 mRNA and protein levels.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing, 400014, PR China.

ABSTRACT

Background: Ketamine is a commonly used clinical anesthetic and a popular recreational drug. However, with the exception of studies about the nervous system, studies about the effect of early ketamine exposure on embryos are rare. Xenopus laevis is a commonly used vertebrate model for assessing teratogenicity. Therefore, we treated Xenopus embryos with ketamine to evaluate its teratogenicity on embryos.

Methods: Xenopus embryos were treated with ketamine from stages 8 to 21. Embryonic and cardiac morphology were analyzed using living embryo imaging and whole-mount RNA in situ hybridization (WMISH). Heart function was measured by heart rate and ventricular shortening fraction (VSF). The mRNA expression levels of several heart development-related genes were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The protein expression levels of XMLC2, phospho-histone H3 (pH3) and histone H3 were determined by western blot.

Results: Ketamine caused concentration-dependent increases in mortality and shortening of body length. At a dose of 0.5 mg/ml, ketamine exposure resulted in cardiac enlargement as the primary manifestation of several malformations: gut defects, a curved axis and shortened body length. Cardiac cells underwent increased proliferation. Moreover, the heart rate and ventricular shortening fraction were decreased, findings indicative of heart dysfunction. XMLC2 expression levels were down-regulated at stages 28, 32/33, 35/36 and 46.

Conclusions: Ketamine exposure during early development has teratogenic effects on Xenopus embryos. The heart enlargement and decreased VSF may result from the down-regulation of XMLC2 mRNA and protein levels. These findings provide new insight into the potential fetal defects induced by ketamine exposure during early pregnancy.

No MeSH data available.


Related in: MedlinePlus