Suppression of spermatogenesis by bisdichloroacetyldiamines is mediated by inhibition of testicular retinoic acid biosynthesis.
Suppression of spermatogenesis by bisdichloroacetyldiamines is mediated by inhibition of testicular retinoic acid biosynthesis.
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DOI：
10.2164/jandrol.110.010751
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发表时间：
2011-01
影响因子：
--
通讯作者：
Griswold MD
中科院分区：
文献类型：
--
作者：
Amory JK;Muller CH;Shimshoni JA;Isoherranen N;Paik J;Moreb JS;Amory DW Sr;Evanoff R;Goldstein AS;Griswold MD
双二氯乙酰二胺 WIN 18,446 可逆地抑制许多物种（包括人类）的精子发生；然而，WIN 18,446 的运行机制尚不清楚。由于视黄酸对于精子发生至关重要，因此我们假设 WIN 18,446 可能通过抑制醛脱氢酶 1a2 (ALDH1a2) 来抑制睾丸内视黄醇（维生素 A）的视黄酸生物合成。我们在成熟雄性兔中研究了 WIN 18,446 对体外 ALDH1a2 酶活性的影响，以及对体内精子发生和生育能力的影响，为期 16 周。 WIN 18,446 在体外显着抑制 ALDH1a2 酶活性，IC50 为 0.3 μM。在体内，雄性兔口服200 mg/kg WIN 18,446 16周后，睾丸内视黄酸浓度显着降低，严重损害精子发生，并导致不育。仅治疗 4 周后，睾丸内视黄酸浓度就明显降低，并且先于精子数量减少和组织样本中成熟生殖细胞的损失。停止治疗后精子数量和生育能力恢复。这些发现表明，WIN 18,446 等双二氯乙酰二胺通过 ALDH1a2 抑制睾丸视黄酸生物合成，可逆地抑制精子发生。这些发现表明 ALDH1a2 是开发可逆、非激素男性避孕药的一个有希望的靶点。
The bisdichloroacetyldiamine WIN 18,446 reversibly inhibits spermatogenesis in many species, including humans; however, the mechanism by which WIN 18,446 functions is unknown. As retinoic acid is essential for spermatogenesis, we hypothesized that WIN 18,446 might inhibit retinoic acid biosynthesis from retinol (vitamin A) within the testes by inhibiting the enzyme aldehyde dehydrogenase 1a2 (ALDH1a2). We studied the effect of WIN 18,446 on ALDH1a2 enzyme activity in vitro, and on spermatogenesis and fertility in vivo, in mature male rabbits for 16 weeks. WIN 18,446 markedly inhibited ALDH1a2 enzyme activity in vitro with an IC50 of 0.3 μM. In vivo, the oral administration of 200 mg/kg WIN 18,446 to male rabbits for 16 weeks significantly reduced intratesticular concentrations of retinoic acid, severely impaired spermatogenesis, and caused infertility. Reduced concentrations of intratesticular retinoic acid were apparent after only 4 weeks of treatment and preceded the decrease in sperm counts and the loss of mature germ cells in tissue samples. Sperm counts and fertility recovered after treatment was discontinued. These findings demonstrate that bisdichloroacetyldiamines such as WIN 18,446 reversibly suppress spermatogenesis via inhibition of testicular retinoic acid biosynthesis by ALDH1a2. These findings suggest that ALDH1a2 is a promising target for the development of a reversible, nonhormonal male contraceptive.
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影响因子：
56.9
作者：
Bowles, J;Knight, D;Koopman, P
通讯作者：
Koopman, P
影响因子：
4.1
作者：
Kane, MA;Chen, N;Napoli, JL
通讯作者：
Napoli, JL
影响因子：
4.8
作者：
KURLANDSKY, SB;GAMBLE, MV;BLANER, WS
通讯作者：
BLANER, WS
DOI：
10.1073/pnas.90.15.7225
发表时间：
1993-08-01
影响因子：
11.1
作者：
LUFKIN, T;LOHNES, D;CHAMBON, P
通讯作者：
CHAMBON, P
DOI：
10.2307/2991522
发表时间：
1998-01-01
期刊：
FAMILY PLANNING PERSPECTIVES
影响因子：
--
作者：
Henshaw, SK
通讯作者：
Henshaw, SK