Adequate supply of thyroid hormones is essential for fetal brain development throughout pregnancy. Hypothyroid fetuses suffer various postnatal disorders ranging from reduced IQ to mental retardation and spasticity. Over the past decade, studies on the delivery of thyroid hormones into the fetal brain have focused on the role of placental and fetal uptake transporters, whereas little is known about the mechanisms that control hormone removal from fetal tissues. This question is clinically relevant, because efflux transport of thyroid hormones may be affected by many drugs given to pregnant women. Moreover, we and others demonstrated that drugs which have been associated with impaired postnatal cognitive development can modulate the expression and activity of efflux transporters known to be involved in the transmembranal transfer of thyroid hormones.
The proposed project will evaluate for the first time the role of maternal and fetal efflux transporters in the delivery of thyroid hormones into the fetal brain. We will also assess the effects of drugs given to pregnant women on maternal and fetal transporter expression and activity. In this proposal we will focus on antiepileptic drugs which are established or suspected behavioral teratogens in humans. Contemporary biochemical and pharmacokinetic studies in pregnant mice and their fetuses will be conducted. The results from this research proposal if successful will represent an important tool for potential clinical translation reducing markedly the risks of newborn defects originated by a lack of or low thyroid hormone concentration in fetal brain.
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