title: Fetal and neonatal iron deficiency exacerbates mild thyroid hormone insufficiency effects on male thyroid hormone levels and brain thyroid hormone-responsive gene expression.
abstract: Fetal/neonatal iron (Fe) and iodine/TH deficiencies lead to similar brain developmental abnormalities and often coexist in developing countries. We recently demonstrated that fetal/neonatal Fe deficiency results in a mild neonatal thyroidal impairment, suggesting that TH insufficiency contributes to the neurodevelopmental abnormalities associated with Fe deficiency. We hypothesized that combining Fe deficiency with an additional mild thyroidal perturbation (6-propyl-2-thiouracil [PTU]) during development would more severely impair neonatal thyroidal status and brain TH-responsive gene expression than either deficiency alone. Early gestation pregnant rats were assigned to 7 different treatment groups: control, Fe deficient (FeD), mild TH deficient (1 ppm PTU), moderate TH deficient (3 ppm PTU), severe TH deficient (10 ppm PTU), FeD/1 ppm PTU, or FeD/3 ppm PTU. FeD or 1 ppm PTU treatment alone reduced postnatal day 15 serum total T4 concentrations by 64% and 74%, respectively, without significantly altering serum total T3 concentrations. Neither treatment alone significantly altered postnatal day 16 cortical or hippocampal T3 concentrations. FeD combined with 1 ppm PTU treatment produced a more severe effect, reducing serum total T4 by 95%, and lowering hippocampal and cortical T3 concentrations by 24% and 31%, respectively. Combined FeD/PTU had a more severe effect on brain TH-responsive gene expression than either treatment alone, significantly altering Pvalb, Dio2, Mbp, and Hairless hippocampal and/or cortical mRNA levels. FeD/PTU treatment more severely impacted cortical and hippocampal parvalbumin protein expression compared with either individual treatment. These data suggest that combining 2 mild thyroidal insults during development significantly disrupts thyroid function and impairs TH-regulated brain gene expression.
authors.affiliation: Department of Pharmacy Practice and Pharmaceutical Sciences (T.W.B., G.W.A.), College of Pharmacy, University of Minnesota Duluth, Duluth, Minnesota 55812; Department of Biomedical Sciences (J.R.P.), University of Minnesota Medical School Duluth, Duluth, Minnesota 55812; Department of Pediatrics and Center for Neurobehavioral Development (M.K.G.), School of Medicine, University of Minnesota, Minneapolis, Minnesota 55454.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Bastian
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Prohaska
authors.forename: Michael K
authors.initials: MK
authors.lastname: Georgieff
authors.forename: Grant W
authors.initials: GW
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism; D000090463:Iron Deficiencies; D008297:Male; D018811:Maternal Exposure; D010320:Parvalbumins / Q000378:metabolism; D011247:Pregnancy; D011441:Propylthiouracil / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D013961:Thyroid Gland / Q000378:metabolism; D013963:Thyroid Hormones / Q000172:deficiency* / Q000378:metabolism*
chemical_list: D010320:Parvalbumins; D012333:RNA, Messenger; D013963:Thyroid Hormones; D011441:Propylthiouracil