Effects of Exposure to Acetaminophen and Ibuprofen on Fetal Germ Cell Development in Both Sexes in Rodent and Human Using Multiple Experimental Systems.
Effects of Exposure to Acetaminophen and Ibuprofen on Fetal Germ Cell Development in Both Sexes in Rodent and Human Using Multiple Experimental Systems.
复制标题
使用多种实验系统，对乙酰氨基酚和布洛芬暴露于啮齿动物和人类性别的胎儿生殖细胞发育的影响。
DOI：
10.1289/ehp2307
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发表时间：
2018-04-16
影响因子：
10.4
通讯作者：
Mitchell RT
中科院分区：
文献类型：
--
作者：
Hurtado-Gonzalez P;Anderson RA;Macdonald J;van den Driesche S;Kilcoyne K;Jørgensen A;McKinnell C;Macpherson S;Sharpe RM;Mitchell RT
怀孕期间使用镇痛药可能会影响内分泌干扰物所针对的胎儿性腺发育的各个方面。我们使用体外和异种移植方法研究了治疗相关剂量的对乙酰氨基酚和布洛芬是否影响人胎儿睾丸/卵巢的生殖细胞（GC）发育。培养早孕期人类胎儿睾丸/卵巢并暴露于对乙酰氨基酚或布洛芬（7 天）。将妊娠中期的人类胎儿睾丸异种移植到小鼠体内，并暴露于对乙酰氨基酚（1 或 7 天）或布洛芬（7 天）。为了确定作用机制，除了体外和体内大鼠模型外，还使用了具有胎儿 GC 特征的人 GC 肿瘤衍生细胞系 (NTera2)。与对照组相比，体外暴露于对乙酰氨基酚 (–28%) 或布洛芬 (–22%) 的妊娠早期人类胎儿睾丸以及暴露于对乙酰氨基酚 (–43%) 或布洛芬 (–49%) 的卵巢中，生殖细胞 () 数量减少。在对宿主小鼠进行 1 或 7 天的处理后，异种移植的妊娠中期人类胎儿睾丸中的对乙酰氨基酚暴露使性母细胞数量分别减少 17% 和 30%。接触镇痛剂或前列腺素受体拮抗剂后，NTera2 细胞数量减少，而激动剂则阻止对乙酰氨基酚诱导的 NTera2 细胞数量减少。暴露于镇痛剂和受体拮抗剂后，GC 多能性基因和调节 DNA/组蛋白甲基化的基因的表达也与对照组不同。在大鼠胎儿睾丸/卵巢培养物中以及怀孕大鼠体内对乙酰氨基酚暴露后观察到基因表达变化。例如，在人 NTera2 细胞、大鼠胎儿睾丸/卵巢培养物中，以及在怀孕大鼠体内暴露于对乙酰氨基酚后，在胎儿睾丸和卵巢中，表观遗传调节剂 TET1 的表达在接触对乙酰氨基酚后增加，这表明在实验模型和物种之间的可翻译性。我们的结果证明了对乙酰氨基酚和布洛芬对 GC/NTera2 细胞的影响，这引起了对人类妊娠期间镇痛剂使用的担忧，值得进一步研究。 https://doi.org/10.1289/EHP2307
Analgesic exposure during pregnancy may affect aspects of fetal gonadal development that are targeted by endocrine disruptors. We investigated whether therapeutically relevant doses of acetaminophen and ibuprofen affect germ cell (GC) development in human fetal testes/ovaries using in vitro and xenograft approaches. First-trimester human fetal testes/ovaries were cultured and exposed to acetaminophen or ibuprofen (7 d). Second-trimester human fetal testes were xenografted into mice and exposed to acetaminophen (1 or 7 d), or ibuprofen (7 d). To determine mechanism of action, a human GC tumor–derived cell line (NTera2) exhibiting fetal GC characteristics was used in addition to in vitro and in vivo rat models. Gonocyte () number was reduced relative to controls in first-trimester human fetal testes exposed in vitro to acetaminophen (–28%) or ibuprofen (–22%) and also in ovaries exposed to acetaminophen (–43%) or ibuprofen (–49%). Acetaminophen exposure reduced gonocyte number by 17% and 30% in xenografted second-trimester human fetal testes after treatment of host mice for 1 or 7 d, respectively. NTera2 cell number was reduced following exposure to either analgesic or prostaglandin () receptor antagonists, whereas agonists prevented acetaminophen-induced reduction in NTera2 cell number. Expression of GC pluripotency genes, and genes that regulate DNA/histone methylation, also differed from controls following analgesic and receptor antagonist exposures. Gene expression changes were observed in rat fetal testis/ovary cultures and after in vivo acetaminophen exposure of pregnant rats. For example, expression of the epigenetic regulator TET1, was increased following exposure to acetaminophen in human NTera2 cells, rat fetal testis/ovary cultures, and in fetal testes and ovaries after in vivo exposure of pregnant rats, indicating translatability across experimental models and species. Our results demonstrate evidence of effects of acetaminophen and ibuprofen on GC/NTera2 cells, which raises concerns about analgesic use during human pregnancy that warrant further investigation. https://doi.org/10.1289/EHP2307