Dissertation
Dissertation > Medicine, health > Obstetrics and Gynaecology > Obstetrics > Pathological pregnancy ( abnormal pregnancy )

Effects of Levothyroxine Treatment on Offspring Brain Development in Pregnant Rats with Subclinical Hypothyroidism

Author LuLi
Tutor DanZhongYan
School China Medical University
Course Internal Medicine
Keywords Subclinical hypothyroidism L-T4 Posterity Brain development Water maze Cell migration Reelin Tenascin - C LICAM Laminin
CLC R714.2
Type PhD thesis
Year 2010
Downloads 222
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Preface subclinical hypothyroidism (Subclinical hypothyroidism, SCH), also known as subclinical hypothyroidism, the overall prevalence in the general population is 4-10%, 5% prevalence rate in pregnant women. Maternal hypothyroidism, especially maternal and fetal hypothyroidism caused by iodine deficiency disorders can lead to children's mental retardation (cretinism) has long been recognized. Man and his colleagues first discovered the minor's mother hypothyroidism can cause offspring intelligence score (intelligence quotient, IQ) reduce 1999 Haddow and Pop scholars found: the mother during pregnancy, elevated TSH or FT4 decreased offspring of lower intelligence score our group's findings also suggest that women 16 to 20 weeks of pregnancy simple subclinical hypothyroidism, simple low T4 the hyperlipidemia and simply TPOAb positive score 8-10 points lower intellectual and motor development in 25-30 months so that future generations are . Mother subclinical hypothyroidism caused offspring intelligence scores decreased exact mechanism is unclear, this study intends to investigate L-thyroxine (L-T4) therapy during pregnancy maternal subclinical hypothyroidism improve the effectiveness of the offspring brain development through animal experiments and The best time for treatment, and to explore its mechanism. 75 Wistar female rats weighing and anesthesia underwent thyroid resection, one month after the post-orbital venous blood test thyroid function, serum TSH higher than normal, but the TT4 is less than the minimum value (lt; 1μg/dL) prompt the thyroidectomy clean successfully established clinical hypothyroidism (CH) model. 15 clinical hypothyroid rat subcutaneous injection containing BSA in PBS; subcutaneous injection of L-T4 0.95μg/100g · d dose 60, nine days after the orbital venous blood test thyroid function, serum TSH is higher than normal, while TT4 levels in the normal range, suggesting that a subclinical hypothyroidism rat (SCH) model is established successfully. 15 Wistar female line thyroidectomy sham operation as a normal control group (C), and subcutaneous injection containing BSA in PBS. Each group model was successfully established with normal male mice at the same time in the same cage mate, the female: male = 2:1, sperm identified as 0 days of gestation when the next morning found the female vaginal suppository or vaginal smear microscopy, denoted by E0. 60 subclinical hypothyroidism in pregnant rat model, in which 15 pregnant rats continue to 0.95μg/100g · d dose subcutaneous injection of L-T4 to postpartum 21 days (P21); remaining 45 rats were in the first 10 days of gestation (E10 ) (n = 15), day 13 (E13) (n = 15) and 17 days (E17) (n = 15) began to 1.25μg/100g · d dose subcutaneous injection of L-T4 to P21; All dams respectively, in the pre-pregnancy, E10, E13, E17, E19 retro-orbital venous plexus blood serum of TSH, TT4, intraperitoneal injection of bromodeoxyuridine (BrdU) 20mg/kg · d E14-E16-day total of 3 days. Childbirth in mind the day is P0. P3 when litter pups merit retention 8, P3, P7 and P40 when monitoring pups weight, offspring brain development related indicators to detect. P45 application of water maze assay pups learning and memory abilities. Nissl staining in the cerebral cortex and hippocampus morphological changes observed under an optical microscope; application of immunohistochemical staining of BrdU distribution, in order to determine the location of the migration of cerebral cortical cells during early pregnancy; application of immunohistochemistry or Western blot Reelin, Tenascin - Semi-quantitative analysis of the C, L1 cell adhesion molecule (LICAM) and laminin. 1, serum of TSH, TT4 level results compared with the sham group, subclinical hypothyroidism group showed serum TSH levels were significantly higher than the sham group (P lt; 0.05), while TT4 levels did not change significantly (P gt ; 0.05), in line with the the subclinical hypothyroidism hormones serological changes. The E10 treatment group, the the E13 treatment group and the E17 treatment group before treatment elevated TSH (P lt; 0.05), TT4 no significant change (P gt; 0.05) is still in subclinical hypothyroidism, serum hormone levels of pregnant rats after treatment shows TSH and TT4 and normal control group of pregnant rats had no significant difference (P gt; 0.05). 2 developmental groups offspring body weight and hormone levels P3 and P7 when the subclinical hypothyroidism pups body weight was significantly lower than normal control group pups (P lt; 0.05) and normal control group P40 when no significant difference than completely hypothyroidism group (P lt; 0.05) (P gt; 0.05); compared completely hypothyroidism pups, P3, P7 and P40 was no significant difference between (P gt; 0.05); hypothyroidism pups shape small, slow weight gain, weight P3, P7 and P40 are lower than normal control group pups (P lt; 0.05). The the E10 treatment group, the the E13 treatment group and the treatment group E17 pups weight in P3, P7 and P40 with normal control group pups had no significant difference (P gt; 0.05), significantly higher than the full hypothyroidism. Thyroid function tests in 40-day-old pups serum TSH hormone levels and serum TT4 hormone levels were not statistically different (P gt; 0.05) is found. Morris water maze Determination of the index analysis hypothyroidism and subclinical hypothyroidism group escape latency with the control group, there were significant differences (P lt; 0.05), compared to 5 day escape latency with the control group, there was still a significant difference (P lt; 0.05). E10 therapy group the pups and E13 treatment group pups in the escape latency of each period of training with the normal control group pups was no significant difference (P gt; 0.05), but at E17 treatment group training in each period escape latency than normal control extend the pups, significant difference (P lt; 0.05). 4 groups pups cortex and hippocampus pathological morphological changes Nissl staining light microscopy results showed that 7-day-old normal control group pups somatosensory cortical layers of nerve cells arranged in dense neat Ⅳ layer to see a typical barrel structure Ⅴ layers, see large pyramidal cells, each cell layer of clear boundaries between subclinical hypothyroidism and completely hypothyroid pups somatosensory cortex no typical performance. The E17 treatment group also true, but the E10 treatment and the E13 starting treatment group pups performance with no significant difference between the normal control group pups; 40-day-old pups have similar results. Cortical thickness measurement results show that when P7 pups had no significant difference (P gt; 0.05), P40 the hypothyroid pups cortex than the normal control group pups were thin (P = 0.000). Normal control group hippocampus CA1 pyramidal cell layer clear boundaries, the E10 treatment group and the the E13 treatment group Aberdeen rats showed no significant difference between the normal control group pups, the treatment group E17, subclinical hypothyroidism group and completely hypothyroidism Aberdeen unclear boundaries between layers of rat hippocampal CA1 neurons. Subclinical hypothyroidism group and completely hypothyroidism hippocampus pyramidal layer (py) thickening of the radiation (ra) layer is thinner (P lt; 0.05) Similarly, the E17 the treatment group, but the the E10 treatment group and E13 treatment similar to the normal control group, the thickness was no significant difference (P gt; 0.05). 5, brain cell migration subclinical hypothyroidism and subclinical hypothyroidism group offspring BrdU labeled cells more widely distributed, the BrdU-labeled cells in the white matter, statistics showed that the number of Ⅵ layer and subcortical white matter of BrdU-labeled cells obvious than the normal control group pups Ⅱ - Ⅲ layer decreased (P lt; 0.05), neural cell migration in abnormal location does not correspond with the date of birth; pups performance of the treatment group E17 with subclinical hypothyroidism group and completely hypothyroidism The pups were similar, but the the the E10 treatment group and the E13 treatment group and normal control group pups were similar (P gt; 0.05). Pups brain Reelin and tenascin-C expression level changes in immune histochemistry staining found: 7-day-old and 40-day-old hypothyroidism, subclinical hypothyroidism group and the E17 treatment pups somatosensory cortex and hippocampus Reelin expression was significantly lower than the control group (P lt; 0.05), E10 and E13 treatment group and the control group had no significant difference. 7-day-old group of hypothyroidism, subclinical hypothyroidism group and the the E17 treatment group Aberdeen mouse somatosensory cortex tenascin-C expression was significantly higher than the normal control group (P lt; 0.05); 40 days old group had no significant difference. Offspring cortex and hippocampus L1CAM, laminin (Laminin) level detected by Western blotting cortex results show, compared with the normal control group, the treatment group E17, subclinical hypothyroidism and hypothyroidism pups cortex L1CAM three the major polypeptide protein expression after birth 3d (P3) was significantly higher (P lt; 0.05), but the E10 and E13 treatment group with no difference between the normal control group; P7 when hypothyroid group the L1CAM 140kDa polypeptide expression was significantly more than normal control group (P lt; 0.05), no difference between the other groups; the P40 when L1CAM the three main polypeptide was no significant difference among the groups. Hippocampus test results show that, compared to the normal control group, the the three polypeptides the hypothyroid pups cortex L1CAM protein expression in the postnatal 3d (P3) was significantly higher, E10, E13, E17 and subclinical hypothyroidism group the L1CAM three polypeptide There were no significant differences between the normal control group (P gt; 0.05); P7 and P40 when the hippocampus of L1CAM the three major polypeptide expression in each group had no significant difference. Cortex and hippocampus test results show that laminin There was no significant difference between groups (P gt; 0.05). Conclusion 1 pregnancy maternal subclinical hypothyroidism will affect the normal development of the offspring, gestational day 10 (E10), E13 and E17 applied L-T4 treatment of female rats to normal thyroid function, can promote the normal development of the body weight of the pups . Maternal hypothyroidism and subclinical hypothyroidism can lead to future generations of learning and memory abilities of serious injury in L-T4 treatment before E13 assays showed no significant effect on offspring pups behavior; E17 after L-T4 treatment still pups behavior of future generations assays indicators impact. 3, the decline in the ability of subclinical hypothyroidism in the offspring of female mice learning and memory may be framed with cell abnormalities of nerve cell migration and positioning E13 begin before L-T4 treatment can prevent the disorder of neuronal migration and positioning. Low thyroid function Cytoarchitecture abnormal neuronal migration and positioning and migration related to an increase of the the related molecule Reelin decline, the rise of tenascin-C and L1CAM, laminin.

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