Relationships between aromatase activity in the brain and gonads and behavioural deficits in homozygous and heterozygous aromatase knockout mice
Relationships between aromatase activity in the brain and gonads and behavioural deficits in homozygous and heterozygous aromatase knockout mice
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DOI：
10.1111/j.1365-2826.2004.01191.x
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发表时间：
2004-05-01
影响因子：
3.2
通讯作者：
Balthazart, J
中科院分区：
文献类型：
--
作者：
Bakker, J;Baillien, M;Balthazart, J
本研究的目的是确定芳香酶敲除 (ArKO) 小鼠的大脑和性腺是否完全缺乏芳香酶活性，并比较野生型和 ArKO 小鼠以及先前显示出多种生殖行为的两性杂合 (HET) 小鼠的芳香酶活性；水平介于野生型和 ArKO 小鼠之间。在成年野生型小鼠视前区-下丘脑匀浆中，芳香酶活性极低，通过氚水测定无法检测到，但在用睾酮治疗 12 天后被诱导。睾酮对男性芳香酶活性的诱导作用明显大于女性。即使在暴露于睾酮 12 天后，无论性别的 ArKO 小鼠的大脑中都没有检测到芳香酶活性，而 HET 小鼠的活性水平介于 ArKO 和野生型之间。在成年 ArKO 雌性的卵巢中也检测不到芳香酶活性，但在野生型卵巢中非常高，在 HET 卵巢中处于中等水平。在野生型小鼠中，即使没有用睾酮进行预处理，在出生当天也能检测到高水平的芳香酶活性。男性的这种新生儿活动高于女性，但女性的大脑中似乎仍显示出大量的雌激素产生。在新生 ArKO 雄性和雌性小鼠的大脑中检测不到芳香酶活性，并且在 HET 小鼠中介于野生型和 ArKO 之间。总之，本研究证实 ArKO 小鼠无法合成任何雌激素，从而验证了 ArKO 小鼠作为研究雌二醇生理作用的有价值的工具。此外，它还表明，HET小鼠的中间行为可能反映了基因剂量对芳香酶表达和活性的影响，芳香酶活性在小鼠的新生儿期和成年期存在性别分化，最后，新生雌性大脑产生大量雌激素，这些雌激素可能在雌性大脑早期的性别分化中发挥重要作用。
The present study was carried out to determine whether aromatase knockout (ArKO) mice are completely devoid of aromatase activity in their brain and gonads and to compare aromatase activity in wild-type and ArKO mice, as well as in heterozygous (HET) mice of both sexes that were previously shown to display a variety of reproductive behaviours; at levels intermediate between wild-type and ArKO mice. Aromatase activity was extremely low, and undetectable by the tritiated water assay, in homogenates of the preoptic area-hypothalamus of adult wild-type mice, but was induced following a 12-day treatment with testosterone. The induction of aromatase activity by testosterone was significantly larger in males than in females. Even after 12 days exposure to testosterone, no aromatase activity was detected in the brain of ArKO mice of either sex whereas HET mice showed intermediate levels of activity between ArKO and wild-type. Aromatase activity was also undetectable in the ovary of adult ArKO females but was very high in the wildtype ovary and intermediate in the HET ovary. In wild-type mice, a high level of aromatase activity was detected on the day of birth even without pretreatment with testosterone. This neonatal activity was higher in males than in females, but females nevertheless appear to display a substantial level of oestrogen production in their brain. Aromatase activity was undetectable in the brain of newborn ArKO males and females and was intermediate between wild-type and ArKO in HET mice. In conclusion, the present study confirms that ArKO mice are unable to synthesize any oestrogens, thereby validating the ArKO mouse as a valuable tool in the study of the physiological roles of oestradiol. In addition, it demonstrates that the intermediate behaviour of HET mice presumably reflects the effect of gene dosage on aromatase expression and activity, that aromatase activity is sexually differentiated in mice during the neonatal period as well as in adulthood and, finally, that the neonatal female brain produces substantial amounts of oestrogens that could play a significant role in the sexual differentiation of the female brain early in life.