Behavioral development in adolescent rats of perinatal hypothyroidism and its relations to androgen receptor gene expression in hippocampus / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the behavioral development in adolescent rats of perinatal hypothyroidism and its relation to androgen receptor (AR) gene expression in the hippocampus.</p><p><b>METHODS</b>Perinatal hypothyroidism was induced by gavages 50 mg/d of propylthiouracil solution in 48 dams starting at embryonic day 15 through the lactation period. Twenty-four pups (M:F=1) of perinatal hypothyroidism were injected intraperitoneally with 2 microg T(4)/100 g BW daily from the day of birth to the age of 21 days (treatment group); 24 pups (M:F=1) without treatment were designated as hypothyroidism group. And 24 normal pups (M:F=1) served as the control group. The effects of perinatal hypothyroidism on the abilities to learn and retain memory traces and on behavior were observed in rats of both sexes at 60 days. Experiments were performed using models of conditioned "open" field test and passive avoidance reflexes. Hippocampus samples were collected and AR mRNA was detected by competitive RT-PCR.</p><p><b>RESULT</b>Perinatal hypothyroidism caused an increase of crossing number and decrease of rearing and defecation in both sexes. In treatment groups, only the crossing number in male didn't reach the normal level (P >0.05). In passive avoidance test, hypothyroidism groups showed more mistakes in both sexes and shorter latencies in males, the females performed better than males (P <0.01). The treatment groups performed significantly better than the age-matched hypothyroidism groups and reached the normal level (P >0.05). AR mRNA levels in hippocampus of hypothyroid group were lower than those of the controls in males, and the levels in treatment groups were significantly higher in comparison with the hypothyroidism groups (P <0.01). There were no significant differences among the three female groups (P >0.05). In male group, there was negative correlation between the number of crossing and AR mRNA in the hippocampus (r=-0.537, P=0.001), negative correlation between the number of mistake and AR mRNA (r=-0.532, P=0.001), and positive correlation between the latency and AR mRNA (r=0.564, P=0.000).</p><p><b>CONCLUSION</b>Perinatal hypothyroidism results in hyperactivity and anti-anxiety effects on adolescent rats, the sex difference is depleted, and also causes learning and memory impairment but the degree of influence higher in male than female. The decreased level of AR mRNA expression in hippocampus contributes to the change of behavioral ability in adolescent male.</p>

Low initial dose of levothyroxine for treatment of congenital hypothyroidism / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To evaluate the results of treatment of infants with congenital hypothyroidism (CH) with a low initial dosage of levothyroxine.</p><p><b>METHODS</b>138 newborns with primary CH detected by neonatal screening were divided into 3 groups according to levels of serum TSH, TT(3) and TT(4): sub-clinical CH (TSH >50 mU/L), mild CH (TT(4) <54 nmol/L), severe CH (TT(4)<54 nmol/L and TT(3)<1.2 nmol/L). The initial dose of levothyroxine was (3.5 +/-1.0) microg/(kg.d) for sub-clinical CH group, (4.3 +/-0.7)microg/(kg.d) for mild CH group and (4.7 +/- 0.6)microg/(kg.d) for severe CH group. Follow-up evaluation was carried out at 1, 2 and 3 months of age by measuring serum levels of TT(3), TT(4) and TSH. The time, when clinical signs and symptoms were eliminated and serum levels of TT(3), TT(4) and TSH normalized, was recorded. Development Quotient (DQ) testing was performed when CH cases were about 2 years old.</p><p><b>RESULTS</b>The mean initial dose of levothyroxine in 138 cases was (4.3 +/-0.9)microg/(kg.d). In one month the serum TT(3) and TT(4) levels returned to normal, while for TSH levels 67.4 % cases reached normal range in 2 months and 84.1 % in 3 months. Two months after therapy, the levels of TT(3) and TT(4) reached to the upper half of normal range and there were no signs or symptoms of hypothyroidism. The time for all cases in 3 groups to reach the normal clinical and biochemical indicators was similar (P=0.925). The dosage for cases with low circulating thyroxine before treatment was higher than that of the other groups (P<0.01). The average DQ score of 18 cases after treatment was 116.7 +/- 17.0.</p><p><b>CONCLUSION</b>he levothyroxine dosage of (4.3 +/- 0.9)microg/(kg.d) is appropriate for the initial treatment of the majority of infants with CH. However it is better to individualize the dosage for each case.</p>

Mechanism for apoptosis of hippocampus neuron induced by hypothyroidism in perinatal rats / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the mechanism for the apoptosis of hippocampus neuron induced by hypothyroidism in perinatal rats.</p><p><b>METHODS</b>Hypothyroidism was induced by administration of propylthiouracil (PTU, 50 mg/d) solution to the dams from gestational day 15 by gavage. Pups from both hypothyroid and control groups were harvested at 1, 5, 10 and 15d, respectively. Blood samples were collected at the time of death for the determination of thyroid hormone. Serum free triiodothyronine (FT(3)) and free thyroxine (FT(4)) were measured by chemoluminescence. Hippocampus specimens were collected from the control and hypothyroid pups.Mitochondia was examined under transmission electron microscopy. Translocation of apoptogenic molecules (Bax, cytochrome C and AIF) and activation of caspase-3 were analyzed by Western Blotting.</p><p><b>RESULT</b>Significantly low circulating FT(3) and FT(4) levels confirmed the hypothyroid status of the experimental pups. Electron microscopy showed that altered morphology of mitochondria significantly increased under hypothyroid conditions. The expression of Bax in the cytosol of hypothyroid pups was higher than that of control pups at all stages of development (P<0.05),and significantly higher in mitochondria (P<0.001). The expression of cytochrome c in the cytosol of hypothyroid pups was significantly higher than that of control pups at all stages of development (1,10 and 15 d:P<0.05, 5d: P<0.001), and lower in mitochondria (P<0.05). The expression of AIF in the cytosol of hypothyroid pups was higher than that of control pups at all stages of development (P<0.001), and significantly lower in mitochondria (1, 5d: P<0.001, 10, 15 d: P<0.01). he expression of caspase-3 P20 in the cytosol of hypothyroid pups was significantly higher as compared with that of the age-matched controls (1, 15d: P<0.01, 5,1 0 d: P<0.001).</p><p><b>CONCLUSION</b>The intrinsic death pathway in mitochondria may be one of the mechanisms with which hypothyroid induces apoptosis of hippocampus neuron in developing rats.</p>

On the behaviour,learning and memory in rats with perinatal hypothyroidism / 中华内分泌代谢杂志

The results of open-field test,step-through passive avoidance task and radial-arm maze experiment showed that changes of locomotor activity,anxiety-related behaviour and ability of learning and memory were associated with the increased apoptosis of neurons in hippocampus in rats with perinatal hypothyroidism.