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

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 (r2=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.

Thyroid hormones in fetal growth and prepartum maturation

“…Similarly, in normal human infants, umbilical T 4 concentrations are positively related to body weight and length at birth (Sack et al 1993, Shields et al 2011. In addition, TR binding in skeletal muscle is lower in newborn runts compared with normal-sized piglets (Dauncey & Geers 1990), and immunostaining for the TR isoforms and thyroid hormone transporter, MCT8, are reduced in the occipital cerebral cortex of IUGR human fetuses (Kilby et al 2000, Chan et al 2014. Collectively, the clinical and experimental findings indicate that bioavailability of thyroid hormones in utero regulates fetal growth by acting as a signal of the nutrient and oxygen supply to the fetus (Fowden & Forhead 2009).…”

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

“…The thyroid hormone transporter MCT8 and the amino acid transporter MCT10 seem to be widely expressed in human tissues. MCT8 expression seems to be of major importance in the brain and placenta for fetal development 21. Human MCT5 and MCT6 protein were found to be expressed in the human intestine (note: Gill et al .…”

“…MCT8 expression seems to be of major importance in the brain and placenta for fetal development. 21 Human MCT5 and MCT6 protein were found to be expressed in the human intestine (note: Gill et al 22 uses former MCT Relevance of the monocarboxylate transporter family in disease and therapy Fisel et al…”

Thyroid Hormones in Fetal Development

“…A reduction of TH blood levels has been reported in IUGR fetus through cordocentesis [ 15 ], and more recently Chan et al [ 41 ] published, for the fi rst time, data on human tissues demonstrating that the transporter MCT8 is less expressed in the central neuro system of IUGR supposing that this abnormality could contribute to the neurodevelopment impairment.…”