Cyclooxygenase 2 (COX2) expression and prostaglandin synthesis in neonatal rat testicular germ cells: Effects of acetaminophen and ibuprofen
Cyclooxygenase 2 (COX2) expression and prostaglandin synthesis in neonatal rat testicular germ cells: Effects of acetaminophen and ibuprofen
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DOI：
10.1111/andr.12727
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发表时间：
2019-11-29
期刊：
影响因子：
4.5
通讯作者：
Culty, Martine
中科院分区：
文献类型：
--
作者：
Manku, Gurpreet;Papadopoulos, Philippos;Culty, Martine
对婴儿的发热通常用醋氨酚或布洛芬治疗，这两种解热镇痛药物抑制环氧合酶（COX），催化前列腺素的产生。婴儿期是新生儿生殖细胞/生殖母细胞分化为精子发生所需的精原干细胞的关键发育期。目的（a）测定生后第3天（PND）大鼠生殖细胞与精原细胞中Cox 2及其相关基因的表达。(b)检查对乙酰氨基酚或布洛芬是否会破坏新生儿生殖细胞功能。(c)确定新生儿生殖细胞是否产生异甘草素，以及这个过程是否被对乙酰氨基酚和布洛芬改变。材料与方法应用基因芯片和qPCR技术检测Cox 2及其相关基因的表达。免疫细胞/组织化学和免疫印迹法测定Cox 2蛋白水平。对乙酰氨基酚和布洛芬对PND 3生殖细胞活力、凋亡、增殖和分化的影响单独和与增殖混合物或分化因子一起检查。结果Cox 2及其相关基因在生殖母细胞和精原细胞中高表达。对乙酰氨基酚和布洛芬不影响生殖细胞存活或凋亡，但它们增加生殖细胞增殖。Iceland显著降低RA诱导的Stra 8表达，表明对分化的抑制作用。黄芪联合RA可降低Cox 2 mRNA和蛋白表达。PGE 2和PGF 2 α由新生儿生殖细胞产生，并被对乙酰氨基酚和布洛芬降低。讨论在RA共处理的生殖细胞中Stra 8表达、Cox 2表达以及PGE 2和PGF 2a产生的伴随减少表明Cox 2在PND 3生殖细胞分化中起作用。对乙酰氨基酚和布洛芬对增殖的影响表明Cox 2与增殖呈负相关。用对乙酰氨基酚或布洛芬治疗新生儿可能会破坏生殖细胞的发育，导致不良的生殖影响。结论了解COX 2在新生儿生殖细胞中的作用以及对乙酰氨基酚和布洛芬治疗婴儿的潜在风险可能有助于预防男性生殖病理。
Background In infants, fever is often treated with acetaminophen or ibuprofen, two antipyretic and analgesic drugs inhibiting cyclooxygenases (COXs), enzymes catalyzing prostaglandin production. Infancy represents a critical developmental period when neonatal germ cells/gonocytes differentiate to spermatogonial stem cells required for spermatogenesis. Objectives (a) Determine the expression of Cox2 and associated genes in postnatal day (PND)3 rat gonocytes compared to spermatogonia. (b) Examine whether acetaminophen or ibuprofen disrupts neonatal gonocyte functions. (c) Determine whether neonatal gonocytes produce prostaglandins and whether this process is altered by acetaminophen and ibuprofen. Materials and methods The expression of Cox2 and related genes was determined by gene arrays and qPCR. Cox2 protein levels were determined by immunocyto/histochemistry and immunoblots. The effects of acetaminophen and ibuprofen on PND3 gonocyte viability, apoptosis, proliferation, and differentiation were examined alone and with a proliferation cocktail or differentiation factor. Prostaglandins were examined by immunocyto/histochemistry and LC-MS. Results Cox2 and related genes are highly expressed in gonocytes and spermatogonia. Acetaminophen and ibuprofen did not affect gonocyte survival or apoptosis, but they increased gonocyte proliferation. Ibuprofen significantly reduced RA-induced Stra8 expression, indicating an inhibitory effect on differentiation. Ibuprofen combined with RA decreased Cox2 mRNA and protein expression. PGE2 and PGF2 alpha were produced by neonatal gonocytes and decreased by acetaminophen and ibuprofen. Discussion The concomitant decrease of Stra8 expression, Cox2 expression, and PGE2 and PGF2a production in gonocytes co-treated with RA suggests that Cox2 plays a role in PND3 gonocyte differentiation. The effects of acetaminophen and ibuprofen on proliferation suggest a negative relationship between Cox2 and proliferation. Treating neonates with acetaminophen or ibuprofen could disrupt gonocyte development, leading to adverse reproductive effects. Conclusion Understanding COX2 role in neonatal gonocytes and the potential risk of acetaminophen and ibuprofen treatment of infants may help prevent male reproductive pathologies.