title: Thyroid hormone-dependent formation of a subcortical band heterotopia (SBH) in the neonatal brain is not exacerbated under conditions of low dietary iron (FeD).
abstract: Thyroid hormones (TH) are critical for brain development and insufficiencies can lead to structural abnormalities in specific brain regions. Administration of the goitrogen propylthiouracil (PTU) reduces TH production by inhibiting thyroperoxidase (TPO), an enzyme that oxidizes iodide for the synthesis of TH. TPO activity is iron (Fe)-dependent and dietary iron deficiency (FeD) also reduces circulating levels of TH. We have previously shown that modest degrees of TH insufficiency induced in pregnant rat dams alters the expression of TH-responsive genes in the cortex and hippocampus of the neonate, and results in the formation of a subcortical band heterotopia (SBH) in the corpus callosum (Royland et al., 2008, Bastian et al., 2014, Gilbert et al., 2014). The present experiment investigated if FeD alone was sufficient to induce a SBH or if FeD would augment SBH formation at lower doses of PTU. One set of pregnant rats was administered 0, 1, 3, or 10ppm of PTU via drinking water starting on gestational day (GD) 6. FeD was induced in a 2nd set of dams beginning on GD2. A third set of dams received the FeD diet from GD2 paired with either 1ppm or 3ppm PTU beginning on GD6. All treatments continued until the time of sacrifice. On PN18, one female pup from each litter was sacrificed and the brain examined for SBH. We observed lower maternal, PN2 and PN18 pup serum T4 in response to PTU. FeD reduced serum T4 in pups on PN16, but did not affect serum T4 in dams or PN2 pups. Neither did FeD in combination with PTU alter T4 levels in dams on PN18 or pups on PN2 compared to PTU treatment alone. By PN16, however more severe T4 reductions were observed in pups when FeD was combined with PTU. SBH increased with increasing dosage of PTU, but counter to our hypothesis, no SBH was detected in the offspring of FeD dams. As such, T4 levels in dams and newborn pups rather than older neonates appear to be a better predictor SBH associated with TH insufficiency. These data indirectly support previous work indicating prenatal TH insufficiency but not postnatal TH insufficiency in offspring is required for SBH formation.
authors.affiliation: Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Spring
authors.affiliation: College of Pharmacy, University of Minnesota, Duluth, MN, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Bastian
authors.affiliation: College of Pharmacy, University of Minnesota, Duluth, MN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: MidContinent Ecology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Duluth, MN, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kosian
authors.affiliation: College of Pharmacy, University of Minnesota, Duluth, MN, USA.
authors.forename: G W
authors.initials: GW
authors.lastname: Anderson
authors.affiliation: Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC, USA. Electronic address: gilbert.mary@epa.gov.
authors.forename: M E
authors.initials: ME
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D013956:Antithyroid Agents / Q000008:administration & dosage; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D000090463:Iron Deficiencies; D019266:Iron, Dietary; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism* / Q000473:pathology*; D011441:Propylthiouracil / Q000008:administration & dosage; D017207:Rats, Sprague-Dawley; D013963:Thyroid Hormones / Q000172:deficiency* / Q000378:metabolism*; D013974:Thyroxine / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism
chemical_list: D013956:Antithyroid Agents; D019266:Iron, Dietary; D013963:Thyroid Hormones; D014284:Triiodothyronine; D011441:Propylthiouracil; D013974:Thyroxine
keywords: Developmental hypothyroidism; FeD; Iron deficiency; Propylthiouracil; Subcortical band heterotopia