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J Physiol Volume 566, Number 2, 467-480, July 15, 2005 DOI: 10.1113/jphysiol.2005.084673
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Maternal nutrient deprivation induces sex-specific changes in thyroid hormone receptor and deiodinase expression in the fetal guinea pig brain

Shiao Y Chan2, Marcus H Andrews1, Rania Lingas1, Chris J McCabe3, Jayne A Franklyn3, Mark D Kilby2 and Stephen G Matthews1

1 Departments of Physiology, Obstetrics and Gynaecology and Medicine, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Canada M5S 1A8
2 Division of Reproductive and Child Health, University of Birmingham, Birmingham Women's Hospital, Edgbaston, Birmingham B15 2TG, UK
3 Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK

Thyroid hormone deprivation during fetal life has been implicated in neurodevelopmental morbidity. In humans, poor growth in utero is also associated with fetal hypothyroxinaemia. In guinea pigs, a short period (48 h) of maternal nutrient deprivation at gestational day (gd) 50 results in fetuses with hypothyroxinaemia and increased brain/body weight ratios. Thyroid hormone action is mediated by nuclear thyroid hormone receptors (TRs) and is dependent upon the prereceptor regulation of supply of triiodothyronine (T3) by deiodinase enzymes. Examination of fetal guinea pig brains using in situ hybridization demonstrated widespread expression of mRNAs encoding TR{alpha}1, {alpha}2 and ß1, with regional colocalization of deiodinase type 2 (D2) mRNA in the developing forebrain, limbic structures, brainstem and cerebellum at gd52. With maternal nutrient deprivation, TR{alpha}1 and ß1 mRNA expression was significantly increased in the male, but decreased in the female fetal hippocampus and cerebellum and other areas showing high TR expression under euthyroid conditions. Maternal nutrient deprivation resulted in elevated D2 mRNA expression in males and females. Deiodinase type 3 (D3) mRNA expression was confined to the shell of the nucleus accumbens, the posterior amygdalohippocampal area, brainstem and cerebellum, and did not change with maternal nutrient deprivation. In conclusion, maternal nutrient deprivation resulted in sex-specific changes in TR mRNA expression and a generalized increase in D2 mRNAs within the fetal brain. These changes may represent a protective mechanism to maintain appropriate thyroid hormone action in the face of fetal hypothyroxinaemia in order to optimize brain development.

(Received 8 February 2005; accepted after revision 25 April 2005; first published online 5 May 2005)
Corresponding author M. D. Kilby: Department of Fetal Medicine, Division of Reproductive and Child Health, University of Birmingham, Level 3, Birmingham Women's Hospital, Metchley Park Road, Edgbaston, Birmingham B15 2TG, UK.  Email: m.d.kilby{at}bham.ac.uk






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