Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China.
Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
Ecotoxicol Environ Saf. 2024 Sep 15;283:116980. doi: 10.1016/j.ecoenv.2024.116980. Epub 2024 Sep 3.
Acetaminophen (APAP), an antipyretic and analgesic commonly used during pregnancy, has been recognized as a novel environmental contaminant. Preliminary evidence suggests that prenatal acetaminophen exposure (PAcE) could adversely affect offspring's gonadal and neurologic development, but there is no systematic investigation on the characteristics of APAP's fetal developmental toxicity.
Pregnant mice were treated with 100 or 400 mg/kg∙d APAP in the second-trimester, or 400 mg/kg∙d APAP in the second- or third-trimester, or different courses (single or multiple) of APAP, based on clinical regimen. The effects of PAcE on pregnancy outcomes, maternal/fetal blood phenotypes, and multi-organ morphological and functional development of fetal mice were analyzed.
PAcE increased the incidence of adverse pregnancy outcomes and altered blood phenotypes including aminotransferases, lipids, and sex hormones in dams and fetuses. The expression of key functional genes in fetal organs indicated that PAcE inhibited hippocampal synaptic development, sex hormone synthesis, and osteogenic and chondrogenic development, but enhanced hepatic lipid synthesis and uptake, renal inflammatory hyperplasia, and adrenal steroid hormone synthesis. PAcE also induced marked pathological alterations in the fetal hippocampus, bone, kidney, and cartilage. The sensitivity rankings of fetal organs to PAcE might be hippocampus/bone > kidney > cartilage > liver > gonad > adrenal gland. Notably, PAcE-induced multi-organ developmental toxicity was more considerable under high-dose, second-trimester, and multi-course exposure and in male fetuses.
This study confirmed PAcE-induced alterations in multi-organ development and function in fetal mice and elucidated its characteristics, which deepens the comprehensive understanding of APAP's developmental toxicity.
醋氨酚（APAP）是一种常用的解热镇痛药，已被确认为新型环境污染物。初步证据表明，产前醋氨酚暴露（PAcE）可能对后代的性腺和神经系统发育产生不利影响，但尚无关于 APAP 胎儿发育毒性特征的系统研究。
根据临床方案，在妊娠中期用 100 或 400mg/kg·d APAP 处理怀孕小鼠，或在妊娠中期和晚期用 400mg/kg·d APAP 处理，或用不同疗程（单次或多次）的 APAP 处理怀孕小鼠。分析 PAcE 对妊娠结局、母体/胎儿血液表型以及胎鼠多器官形态和功能发育的影响。
PAcE 增加了不良妊娠结局的发生率，并改变了母体和胎儿的血液表型，包括转氨酶、脂质和性激素。胎儿器官中关键功能基因的表达表明，PAcE 抑制了海马突触发育、性激素合成以及成骨和软骨发育，但增强了肝内脂质合成和摄取、肾炎症性增生以及肾上腺甾体激素合成。PAcE 还导致胎鼠海马、骨骼、肾脏和软骨出现明显的病理改变。胎儿器官对 PAcE 的敏感性排序可能为海马/骨骼＞肾脏＞软骨＞肝脏＞性腺＞肾上腺。值得注意的是，高剂量、妊娠中期和多次暴露以及雄性胎儿中，PAcE 引起的多器官发育毒性更为显著。
本研究证实了 PAcE 可引起胎鼠多器官发育和功能改变，并阐明了其特征，加深了对 APAP 发育毒性的全面认识。
