Is periventricular heterotopia a useful endpoint for developmental thyroid hormone system disruption in mouse toxicity studies?

In rats, hypothyroidism during fetal and neonatal development can disrupt neuronal migration and induce the formation of periventricular heterotopia in the brain. However, it remains uncertain if heterotopia also manifest in mice after developmental hypothyroidism and whether they could be used as a toxicological endpoint to detect TH-mediated effects caused by TH system disrupting chemicals. Here, we performed a mouse study where we induced severe hypothyroidism by exposing pregnant mice (n = 3) to a very high dose of propylthiouracil (PTU) (1500 ppm) in the diet. This, to obtain best chances of detecting heterotopia. We found what appears to be very small heterotopia in 4 out of the 8 PTU-exposed pups. Although the incidence rate could suggest some utility for this endpoint, the small size of the ectopic neuronal clusters at maximum hypothyroidism excludes the utility of heterotopia in mouse toxicity studies aimed to detect TH system disrupting chemicals. On the other hand, parvalbumin expression was manifestly lower in the cortex of hypothyroid mouse offspring demonstrating that offspring TH-deficiency caused an effect on the developing brain. Based on overall results, we conclude that heterotopia formation in mice is not a useful toxicological endpoint for examining TH-mediated developmental neurotoxicity.

Automated summary

In rats, hypothyroidism during fetal and neonatal development can lead to periventricular heterotopia formation in the brain. This study investigated whether this also occurs in mice and if it could be used as a toxicological endpoint for assessing thyroid hormone (TH) disrupting chemicals. Severe hypothyroidism was induced in pregnant mice using propylthiouracil (PTU), and although small heterotopia were observed in some offspring, their limited size makes them unsuitable for studying TH-mediated developmental neurotoxicity. However, decreased parvalbumin expression in the cortex of hypothyroid mice suggests an effect on brain development.