MCT8-AHDS Foundation

MCT 8 in human fetal cerebral cortex is reduced in severe intrauterine growth restriction

Shiao Y. Chan, Laura A. Hancox, Azucena Martín-Santos, Laurence S. Loubière , Merlin N.M. Walter, Ana-Maria González, Phillip M. Cox, Ann Logan, Christopher J. McCabe , Jayne A. Franklyn, Mark D. Kilby
Abstract: 

The importance of the thyroid hormone (TH) transporter, monocarboxylate transporter (MCT8), to human neurodevelopment is highlighted by findings of severe global neurological impairment in subjects with MCT8 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 TH receptor expression. We postulate that altered MCT8 expression is implicated in this pathophysiology and sought to quantify changes in cortical MCT8 expression with IUGR. Firstly, MCT8 immunohistochemistry was performed on occipital and parietal cerebral cortex sections from appropriately grown for gestational age (AGA) human fetuses between 19 weeks gestation and term.  Secondly, MCT8 immunostaining in the occipital cortex of stillborn IUGR human fetuses at 24-28 weeks gestation were objectively compared with gestationally-matched AGA fetuses. Fetuses demonstrated widespread MCT8 expression in neurons within the cortical plate and subplate, in the ventricular and subventricular zones, epithelium of the choroid plexus and ependyma, and microvessel wall.  When complicated by IUGR, fetuses showed a significant 5-fold reduction in the percentage area of cortical plate immunostained with MCT8 compared with AGA fetuses (p<0.05) but there was no significant difference in the proportion of subplate microvessels immunostained. Cortical MCT8 expression negatively correlated with the severity of IUGR indicated by brain:liver weight ratios (r236 =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.