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MCT8 expression in human fetal cerebral cortex is reduced in severe intrauterine growth restriction.

Chan SY, Hancox LA, Martín-Santos A, Loubière LS, Walter MN, González AM, Cox PM, Logan A, McCabe CJ, Franklyn JA, Kilby MD - J. Endocrinol. (2014)

Bottom Line: Intrauterine growth restriction (IUGR), usually due to uteroplacental failure, is associated with milder neurodevelopmental deficits, which have been partly attributed to dysregulated TH action in utero secondary to reduced circulating fetal TH concentrations and decreased cerebral thyroid hormone receptor expression.When complicated by IUGR, fetuses showed a significant fivefold reduction in the percentage area of cortical plate immunostained for MCT8 compared with AGA fetuses (P<0.05), but there was no significant difference in the proportion of subplate microvessels immunostained.Our results support the hypothesis that a reduction in MCT8 expression in the IUGR fetal brain could further compromise TH-dependent brain development.

View Article: PubMed Central - PubMed

Affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK Department of Pathology Fetal Medicine Centre, Birmingham Women's NHS Foundation Trust, Edgbaston, Birmingham B15 2TG, UK.

ABSTRACT
The importance of the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), to human neurodevelopment is highlighted by findings of severe global neurological impairment in subjects with MCT8 (SLC16A2) mutations. Intrauterine growth restriction (IUGR), usually due to uteroplacental failure, is associated with milder neurodevelopmental deficits, which have been partly attributed to dysregulated TH action in utero secondary to reduced circulating fetal TH concentrations and decreased cerebral thyroid hormone receptor expression. We postulate that altered MCT8 expression is implicated in this pathophysiology; therefore, in this study, we sought to quantify changes in cortical MCT8 expression with IUGR. First, MCT8 immunohistochemistry was performed on occipital and parietal cerebral cortex sections obtained from appropriately grown for gestational age (AGA) human fetuses between 19 weeks of gestation and term. Secondly, MCT8 immunostaining in the occipital cortex of stillborn IUGR human fetuses at 24-28 weeks of gestation was objectively compared with that in the occipital cortex of gestationally matched AGA fetuses. Fetuses demonstrated widespread MCT8 expression in neurons within the cortical plate and subplate, in the ventricular and subventricular zones, in the epithelium of the choroid plexus and ependyma, and in microvessel wall. When complicated by IUGR, fetuses showed a significant fivefold reduction in the percentage area of cortical plate immunostained for MCT8 compared with AGA fetuses (P<0.05), but there was no significant difference in the proportion of subplate microvessels immunostained. Cortical MCT8 expression was negatively correlated with the severity of IUGR indicated by the brain:liver weight ratios (r(2)=0.28; P<0.05) at post-mortem. Our results support the hypothesis that a reduction in MCT8 expression in the IUGR fetal brain could further compromise TH-dependent brain development.

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(A) Correlation between the relative cortical plate area immunostained for MCT8 and the relative proportion of microvessels immunostained for MCT8 in IUGR (black dots) and AGA (white squares) fetuses. A significant positive correlation was observed when all the samples were considered together (dashed line) and when only the IUGR samples were considered on their own (straight line), but there was no significant correlation when only among the AGA samples were considered on their own (dashed and dotted line). (B) Correlation between the relative cortical plate area immunostained for MCT8 and the brain:liver weight ratio. A negative correlation was observed when all the samples were considered together. Statistically significant differences are **P<0.01, *P<0.05.
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fig4: (A) Correlation between the relative cortical plate area immunostained for MCT8 and the relative proportion of microvessels immunostained for MCT8 in IUGR (black dots) and AGA (white squares) fetuses. A significant positive correlation was observed when all the samples were considered together (dashed line) and when only the IUGR samples were considered on their own (straight line), but there was no significant correlation when only among the AGA samples were considered on their own (dashed and dotted line). (B) Correlation between the relative cortical plate area immunostained for MCT8 and the brain:liver weight ratio. A negative correlation was observed when all the samples were considered together. Statistically significant differences are **P<0.01, *P<0.05.

Mentions: However, there was a significant positive correlation between the area of cortical plate MCT8 immunostaining and the proportion of microvessels stained in the subplate (correlation coefficient=0.71, r2=0.27; P<0.01) when all the samples were analyzed together. The positive correlation remained significant within the IUGR group (correlation coefficient=0.75, r2=0.12; P<0.05; Fig. 4A), but there was no significant correlation within the AGA cohort on its own.


MCT8 expression in human fetal cerebral cortex is reduced in severe intrauterine growth restriction.

Chan SY, Hancox LA, Martín-Santos A, Loubière LS, Walter MN, González AM, Cox PM, Logan A, McCabe CJ, Franklyn JA, Kilby MD - J. Endocrinol. (2014)

(A) Correlation between the relative cortical plate area immunostained for MCT8 and the relative proportion of microvessels immunostained for MCT8 in IUGR (black dots) and AGA (white squares) fetuses. A significant positive correlation was observed when all the samples were considered together (dashed line) and when only the IUGR samples were considered on their own (straight line), but there was no significant correlation when only among the AGA samples were considered on their own (dashed and dotted line). (B) Correlation between the relative cortical plate area immunostained for MCT8 and the brain:liver weight ratio. A negative correlation was observed when all the samples were considered together. Statistically significant differences are **P<0.01, *P<0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921694&req=5

fig4: (A) Correlation between the relative cortical plate area immunostained for MCT8 and the relative proportion of microvessels immunostained for MCT8 in IUGR (black dots) and AGA (white squares) fetuses. A significant positive correlation was observed when all the samples were considered together (dashed line) and when only the IUGR samples were considered on their own (straight line), but there was no significant correlation when only among the AGA samples were considered on their own (dashed and dotted line). (B) Correlation between the relative cortical plate area immunostained for MCT8 and the brain:liver weight ratio. A negative correlation was observed when all the samples were considered together. Statistically significant differences are **P<0.01, *P<0.05.
Mentions: However, there was a significant positive correlation between the area of cortical plate MCT8 immunostaining and the proportion of microvessels stained in the subplate (correlation coefficient=0.71, r2=0.27; P<0.01) when all the samples were analyzed together. The positive correlation remained significant within the IUGR group (correlation coefficient=0.75, r2=0.12; P<0.05; Fig. 4A), but there was no significant correlation within the AGA cohort on its own.

Bottom Line: Intrauterine growth restriction (IUGR), usually due to uteroplacental failure, is associated with milder neurodevelopmental deficits, which have been partly attributed to dysregulated TH action in utero secondary to reduced circulating fetal TH concentrations and decreased cerebral thyroid hormone receptor expression.When complicated by IUGR, fetuses showed a significant fivefold reduction in the percentage area of cortical plate immunostained for MCT8 compared with AGA fetuses (P<0.05), but there was no significant difference in the proportion of subplate microvessels immunostained.Our results support the hypothesis that a reduction in MCT8 expression in the IUGR fetal brain could further compromise TH-dependent brain development.

View Article: PubMed Central - PubMed

Affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK Department of Pathology Fetal Medicine Centre, Birmingham Women's NHS Foundation Trust, Edgbaston, Birmingham B15 2TG, UK.

ABSTRACT
The importance of the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), to human neurodevelopment is highlighted by findings of severe global neurological impairment in subjects with MCT8 (SLC16A2) mutations. Intrauterine growth restriction (IUGR), usually due to uteroplacental failure, is associated with milder neurodevelopmental deficits, which have been partly attributed to dysregulated TH action in utero secondary to reduced circulating fetal TH concentrations and decreased cerebral thyroid hormone receptor expression. We postulate that altered MCT8 expression is implicated in this pathophysiology; therefore, in this study, we sought to quantify changes in cortical MCT8 expression with IUGR. First, MCT8 immunohistochemistry was performed on occipital and parietal cerebral cortex sections obtained from appropriately grown for gestational age (AGA) human fetuses between 19 weeks of gestation and term. Secondly, MCT8 immunostaining in the occipital cortex of stillborn IUGR human fetuses at 24-28 weeks of gestation was objectively compared with that in the occipital cortex of gestationally matched AGA fetuses. Fetuses demonstrated widespread MCT8 expression in neurons within the cortical plate and subplate, in the ventricular and subventricular zones, in the epithelium of the choroid plexus and ependyma, and in microvessel wall. When complicated by IUGR, fetuses showed a significant fivefold reduction in the percentage area of cortical plate immunostained for MCT8 compared with AGA fetuses (P<0.05), but there was no significant difference in the proportion of subplate microvessels immunostained. Cortical MCT8 expression was negatively correlated with the severity of IUGR indicated by the brain:liver weight ratios (r(2)=0.28; P<0.05) at post-mortem. Our results support the hypothesis that a reduction in MCT8 expression in the IUGR fetal brain could further compromise TH-dependent brain development.

Show MeSH
Related in: MedlinePlus