Al-Bader, Maie Dawoud; (1999) Sex steroid hormone action in fetal rat brain: Influence of the early intrauterine thyroid hormone environment. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Thyroid hormones, in particular thyroxine, traverse the placenta from mother to fetus during pregnancy and exert influences critical to normal fetal development. Moreover, sex steroid hormones play a critical role during brain development and thyroid hormone deficiency in postnatal progeny has been shown to affect the expression of sex steroid receptors in some tissues, including the brain. Thus, whether a fetus will develop neurological cretinism at birth may depend upon the degree of intrauterine hypothyroxinemia and the sex steroid concentration and sex steroid receptors in utero and beyond. The main aim of this project was to examine the influence of maternal hypothyroxinemia on estradiol (E) and progesterone (P) levels in maternal, fetal and postnatal tissues, as well as the expression of estrogen and progesterone receptor (ER and PR) isoforms in fetal rat brain. ER and PR mRNA and protein expression were studied using RT-PCR and Western blotting methodologies, respectively. Moreover, the expression of several housekeeping genes was studied to see whether the effect of maternal hypothyroxinemia on transcription is a general or selective effect. Maternal hypothyroxinemia resulted in impaired fetal and early postnatal growth, however, placental growth was normal. Matemal hypothyroxinemia resulted in decreased maternal serum estradiol levels at 14 dg and elevated amniotic fluid estradiol levels at 21 dg. Moreover, fetal brain and carcass estradiol levels were decreased at 16 dg and elevated in brain and liver at 21 dg in the experimental group. The decreased estradiol levels at 16 dg in fetal brain was accompanied by decreased ERα and β mRNA levels and ERα protein levels in the nuclear fraction. The change in ERα and β mRNA expression, prior to the onset of fetal thyroid hormone synthesis are selective as RT-PCR revealed no effect on the expression of housekeeping genes. Postnatal rats studied were euthyroid however E levels were elevated at 30 dpn in females from TX dams probably due to in utero effect. In contrast, no effect was observed for PR expression in fetal brain or P hormone levels in maternal and postnatal serum, amniotic fluid or fetal tissue. This thesis has shown that indeed thyroid hormone deficiency in utero has deleterious effects both on E hormone levels and on ER expression before the onset of fetal thyroid function. Moreover, this effect is carried on postnatally so that serum E hormone levels in females were altered.

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