Department of Pediatric Surgery, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Anesthesiology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Toxicol Lett. 2021 Oct 15;351:65-77. doi: 10.1016/j.toxlet.2021.08.008. Epub 2021 Aug 25.
Phthalates are plasticizers widely found in the environment. They are potential endocrine disruptors. Bis(2-butoxyethyl) phthalate (BBOP) is a unique phthalate that contains oxygen atoms in the carbon backbone. Little is known about its reproductive and developmental toxicity. The objective of this study was to determine the effect of BBOP on fetal Leydig cell development after in utero exposure to rats. Sprague Dawley pregnant dams were randomly allocated into 6 groups, and were gavaged with BBOP (0, 10, 100, 250, 500, and 1000 mg/kg body weight/day) from gestational day (GD) 14-21. Seven of the 8 dams in the 1000 mg/kg BBOP group died before giving birth. Twelve of the 20 dams in the 500 mg/kg BBOP group had whole litter loss. BBOP significantly reduced the body weight of dams and male offspring and serum testosterone level and anogenital distance of male fetus on GD 21 at 500 mg/kg. BBOP markedly increased fetal Leydig cell proliferation and number at 500 mg/kg while inducing their abnormal aggregation at 250 and 500 mg/kg. BBOP down-regulated the expression of Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, Hsd17b3, Insl3, and Nr5a1 at various doses while up-regulating the expression of Sertoli cell gene Fshr and Sox9. The phosphorylation of AKT1, AKT2, and ERK1/2 was also markedly reduced by BBOP. In conclusion, BBOP in utero exposure can disrupt fetal Leydig cell development, possibly via the mechanism that may include inhibiting the phosphorylation of AKT1, AKT2, and ERK1/2.
邻苯二甲酸酯是环境中广泛存在的增塑剂。它们是潜在的内分泌干扰物。双（2-丁氧基乙基）邻苯二甲酸酯（BBOP）是一种独特的邻苯二甲酸酯，其碳主链中含有氧原子。关于其生殖和发育毒性知之甚少。本研究的目的是确定宫内暴露于大鼠后 BBOP 对胎儿睾丸间质细胞发育的影响。Sprague Dawley 妊娠大鼠随机分为 6 组，从妊娠第 14-21 天每天灌胃 BBOP（0、10、100、250、500 和 1000mg/kg 体重）。1000mg/kg BBOP 组的 8 只孕鼠中有 7 只在分娩前死亡。500mg/kg BBOP 组的 20 只孕鼠中有 12 只全部产仔丢失。BBOP 显著降低了孕鼠和雄性仔鼠的体重以及雄性胎儿在 GD21 时的血清睾酮水平和肛殖距，在 500mg/kg 时显著增加了胎儿睾丸间质细胞的增殖和数量，而在 250 和 500mg/kg 时诱导其异常聚集。BBOP 下调了 Lhcgr、Scarb1、Star、Cyp11a1、Hsd3b1、Cyp17a1、Hsd17b3、Insl3 和 Nr5a1 的表达，同时上调了 Sertoli 细胞基因 Fshr 和 Sox9 的表达。BBOP 还明显降低了 AKT1、AKT2 和 ERK1/2 的磷酸化。总之，BBOP 宫内暴露可破坏胎儿睾丸间质细胞发育，其机制可能包括抑制 AKT1、AKT2 和 ERK1/2 的磷酸化。
