Ahmed O M, Ahmed R G, El-Gareib A W, El-Bakry A M, Abd El-Tawab S M
Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt.
Int J Dev Neurosci. 2012 Oct;30(6):517-37. doi: 10.1016/j.ijdevneu.2012.04.005. Epub 2012 Jun 1.
Excessive concentrations of free radicals in the developing brain may lead to neurons maldevelopment and neurons damage and death. Thyroid hormones (THs) states play an important role in affecting the modulation of oxidative stress and antioxidant defense system. Thus, the objective of this study was to clarify the effect of hypothyroidism and hyperthyroidism in rat dams on the neurons development of different brain regions of their offspring at several postnatal weeks in relation to changes in the oxidative stress and antioxidant defense system. The adult female rats were administered methimazole (MMI) in drinking water (0.02% w/v) from gestation day 1 to lactation day 21 to induce hypothyroidism and exogenous thyroxine (T4) in drinking water (0.002% w/v) beside intragastric incubation of 50--200 T4 μg/kg body weight (b. wt.) to induce hyperthyroidism. In normal female rats, the sera total thyroxine (TT4) and total triiodothyronine (TT3) levels were detectably increased at day 10 post-partum than those at day 10 of pregnancy. Free thyroxine (FT4), free triiodothyronine (FT3), thyrotropin (TSH) and growth hormone (GH) concentrations in normal offspring were elevated at first, second and third postnatal weeks in an age-dependent manner. In hypothyroid group, a marked depression was observed in sera of dam TT3 and TT4 as well as offspring FT3, FT4 and GH, while there was a significant increase in TSH level with the age progress. The reverse pattern to latter state was recorded in hyperthyroid group. Concomitantly, in control offspring, the rate of neuron development in both cerebellar and cerebral cortex was increased in its density and complexity with age progress. This development may depend, largely, on THs state. Both maternal hypothyroidism and hyperthyroidism caused severe growth retardation in neurons of these regions of their offspring from the first to third weeks. Additionally, in normal offspring, seven antioxidant enzymes, four non-enzymatic antioxidants and one oxidative stress marker (lipid peroxidation, LPO) followed a synchronized course of alterations in cerebrum, cerebellum and medulla oblongata. In both thyroid states, the oxidative damage has been demonstrated by the increased LPO and inhibition of enzymatic and non-enzymatic antioxidants in most examined ages and brain regions. These disturbances in the antioxidant defense system led to deterioration in the neuronal maturation and development. In conclusion, it can be suggested that the maldevelopment of neurons and dendrites in different brain regions of offspring of hypothyroid and hyperthyroid mother rat dams may be attributed, at least in part, to the excess oxidative stress and deteriorated antioxidant defense system in such conditions.
发育中的大脑中自由基浓度过高可能导致神经元发育异常、损伤及死亡。甲状腺激素（THs）状态在影响氧化应激调节和抗氧化防御系统方面发挥着重要作用。因此，本研究的目的是阐明妊娠大鼠甲状腺功能减退和亢进对其后代在出生后几周不同脑区神经元发育的影响，以及与氧化应激和抗氧化防御系统变化的关系。成年雌性大鼠从妊娠第1天至哺乳期第21天饮用含甲巯咪唑（MMI）（0.02% w/v）的水以诱导甲状腺功能减退，饮用含外源性甲状腺素（T4）（0.002% w/v）的水并胃内注射50 - 200 μg/kg体重（b.wt.）的T4以诱导甲状腺功能亢进。在正常雌性大鼠中，产后第10天血清总甲状腺素（TT4）和总三碘甲状腺原氨酸（TT3）水平比妊娠第10天可检测到升高。正常后代的游离甲状腺素（FT4）、游离三碘甲状腺原氨酸（FT3）、促甲状腺激素（TSH）和生长激素（GH）浓度在出生后第一、第二和第三周以年龄依赖性方式升高。在甲状腺功能减退组中，母鼠血清TT3和TT4以及后代FT3、FT4和GH显著降低，而随着年龄增长TSH水平显著升高。甲状腺功能亢进组记录到与后一种状态相反的模式。同时，在对照后代中，随着年龄增长，小脑和大脑皮质的神经元发育速率在密度和复杂性方面均增加。这种发育可能在很大程度上取决于THs状态。母鼠甲状腺功能减退和亢进均导致其后代这些区域的神经元从第一周龄到第三周龄严重生长迟缓。此外，在正常后代中，大脑、小脑和延髓中的七种抗氧化酶、四种非酶抗氧化剂和一种氧化应激标志物（脂质过氧化，LPO）遵循同步变化过程。在两种甲状腺状态下，在大多数检测的年龄和脑区中，LPO增加以及酶促和非酶促抗氧化剂受到抑制均表明存在氧化损伤。抗氧化防御系统的这些紊乱导致神经元成熟和发育恶化。总之，可以认为甲状腺功能减退和亢进的母鼠后代不同脑区神经元和树突的发育异常可能至少部分归因于这种情况下过度的氧化应激和恶化的抗氧化防御系统。
