Perinatal exposure to propylthiouracil (PTU), but not DE-71, induce heterotopia in the brain despite similar effects on serum T4 levels

Thyroid hormones (TH) are crucial for brain development and low maternal serum thyroxine is associated with adverse effects in their children. These effects can manifest as lower IQ, delayed motor development and increased risk of neurobehavioral disorders such as autism and schizophrenia. Concurrently, a number of environmental chemicals can interfere with thyroid hormone availability and action, raising concerns that these chemicals can disturb thyroid hormone balance and adversely affect child brain development. Propylthiouracil (PTU) exposure of pregnant and lactating rats decrease serum thyroxine (T4) levels in dams and offspring, and induce a range of effects in the offspring’s brain. Here, we show that offspring of PTU-exposed dams had periventricular heterotopia, a congenital malformation of the brain. These are irreversible clusters of ectopic neurons in the corpus callosum, which form, in a dose dependent manner, as a result of reduced perinatal T4 levels. We compared heterotopia formation after PTU exposure with that of two other suspected thyroid disrupters: the UV-filter octyl methoxycinnamate (OMC) and a mixture of brominated flame retardants (DE-71). Only PTU induced heterotopia, even though DE-71 reduced T4 levels in the offspring to a similar degree (~75% reduction). Expression of a battery of thyroid hormone responsive genes was analyzed in the pup cortex as potential biomarkers of concurrent TH action. PTU reduced gene expression in a dose-dependent manner, whereas the low serum T4 levels in DE-71 offspring did not alter expression levels. On the other hand, OMC altered gene expression at a time when there was no change in TH levels. This suggests that circulating serum T4 levels, altered by environmental chemicals, are not necessarily reflecting thyroid hormone action in the brain. In order to protect the fetus and the developing child from thyroid hormone disrupting chemicals, future studies should elucidate both adverse effects and the conditions allowing for effects to eventuate.