title: The effect of maternal subclinical hypothyroidism during pregnancy on brain development in rat offspring.
abstract: BACKGROUND
  Maternal thyroid hormones (THs), especially thyroxine (T(4)), are crucial to early brain development in the mammalian embryo. Epidemiological studies and case reports have shown that maternal subclinical hypothyroidism may result in significant negative effects on pregnancy and neurodevelopment of the fetus. To understand the mechanism responsible for these neurological alterations, we induced maternal subclinical hypothyroidism in pregnant rats. Behavior and several genes that are under the control of THs were evaluated in the offspring of TH-deficient rats.
  
  
  METHODS
  A total of 60 female rats were divided into three groups: (i) maternal subclinical hypothyroidism (total thyroidectomy with T(4) infusion), (ii) maternal hypothyroidism (total thyroidectomy without T(4) infusion), and (iii) control (sham operated). All rats were mated 10 days after the start of infusion. The infusion continued until 10 days postpartum. Pups were sacrificed at postnatal day 3 (PND 3), PND 7, and PND 21. The hippocampus was collected and tested for brain-derived neurotrophic factor (BDNF) and Rap1 protein expression by Western blotting and for BDNF and neural cell adhesion molecule mRNA expression by real-time polymerase chain reaction. On PND 41-PND 49, rat pups explored the Morris water maze. Time spent in the quadrant previously containing the platform was recorded.
  
  
  RESULTS
  This study found decreases in BDNF mRNA expression (on PND 3) and protein level (on PND 3 and PND 7) in hippocampi of pups from subclinical hypothyroidism dams (p < 0.05). Rap1 protein expression was higher in maternal subclinical hypothyroidism offspring than in control offspring at PND 7 and PND 21. No change was observed in neural cell adhesion molecule mRNA expression in the maternal subclinical hypothyroidism offspring. In addition, results from the Morris water maze revealed that pups from the subclinical hypothyroidism dams showed deficits in long-term memory, spending less time in the platform quadrant (p < 0.05) during testing. There was a trend toward a deficit in short-term memory (p > 0.05) in this group as well.
  
  
  CONCLUSIONS
  The long-term memory deficits of pups born to maternal subclinical hypothyroidism dams likely related with decreasing in BDNF mRNA expression and protein level as well as increasing in Rap1 protein expression in hippocampi.
authors.affiliation: The Institute of Endocrinology, The First Affiliated Hospital, China Medical University , Shenyang, People's Republic of China.
authors.forename: Dijie
authors.initials: D
authors.lastname: Liu
authors.forename: Weiping
authors.initials: W
authors.lastname: Teng
authors.forename: Zhongyan
authors.initials: Z
authors.lastname: Shan
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Yu
authors.forename: Yun
authors.initials: Y
authors.lastname: Gao
authors.forename: Sen
authors.initials: S
authors.lastname: Wang
authors.forename: Chenling
authors.initials: C
authors.lastname: Fan
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology / Q000254:growth & development*; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D007037:Hypothyroidism / Q000150:complications* / Q000175:diagnosis*; D018782:Maze Learning; D011247:Pregnancy; D011248:Pregnancy Complications / Q000175:diagnosis; D011270:Pregnancy, Animal; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013963:Thyroid Hormones / Q000172:deficiency; D013974:Thyroxine / Q000378:metabolism
chemical_list: D013963:Thyroid Hormones; D013974:Thyroxine