青春期乳腺分支形态发生是一种激素调节的过程,容易暴露于具有内分泌干扰能力的化学物质中,例如UV过滤剂二苯甲酮-3(BP3)。我们的目的是评估子宫内或体外暴露于BP3是否会改变雌性小鼠乳腺的分支形态发生。为此,从妊娠日(GD)8.5至GD18.5,妊娠小鼠皮肤暴露于BP3(0.15或50mg/kg/天)。芝麻油处理用作对照。在出生后第45天研究了后代乳腺的变化。Further,未处理小鼠的乳腺类器官在分支诱导条件下培养,并暴露于BP39天(1×10-6M,1×10-9米,或1×10-12M,0.01%乙醇作为对照)以评估分支进程。在子宫内暴露于BP3的小鼠显示出降低的孕酮受体(PR)和WNT4的mRNA水平。然而,雌二醇和孕酮血清水平,乳腺组织形态学,扩散,雌激素受体α(ESR1)和PR的蛋白表达无明显改变。有趣的是,体外直接暴露于BP3也降低了PR的mRNA水平,RANKL,和双调蛋白而不影响分支进程。大多数影响是在暴露于50mg/kg/天或1×10-6MBP3后发现的,这两者都与人体防晒霜的应用有关。总之,在我们的模型中,暴露于BP3不会损害乳腺分支形态发生。然而,BP3影响PR转录表达及其下游介质,表明暴露于BP3可能会影响乳腺的其他发育阶段。
Pubertal mammary branching morphogenesis is a hormone-regulated process susceptible to exposure to chemicals with endocrine disruptive capacity, such as the UV-filter benzophenone-3 (BP3). Our aim was to assess whether intrauterine or in vitro exposure to BP3 modified the branching morphogenesis of the female mouse mammary gland. For this, pregnant mice were dermally exposed to BP3 (0.15 or 50 mg/kg/day) from gestation day (GD) 8.5 to GD18.5. Sesame oil treatment served as control. Changes of the mammary glands of the offspring were studied on postnatal day 45. Further, mammary organoids from untreated mice were cultured under branching induction conditions and exposed for 9 days to BP3 (1 × 10-6 M, 1 × 10-9 M, or 1 × 10-12 M with 0.01% ethanol as control) to evaluate the branching progression. Mice that were exposed to BP3 in utero showed decreased mRNA levels of progesterone receptor (PR) and WNT4. However, estradiol and progesterone serum levels, mammary histomorphology, proliferation, and protein expression of estrogen receptor alpha (ESR1) and PR were not significantly altered. Interestingly, direct exposure to BP3 in vitro also decreased the mRNA levels of PR, RANKL, and amphiregulin without affecting the branching progression. Most effects were found after exposure to 50 mg/kg/day or 1 × 10-6 M of BP3, both related to sunscreen application in humans. In conclusion, exposure to BP3 does not impair mammary branching morphogenesis in our models. However, BP3 affects PR transcriptional expression and its downstream mediators, suggesting that exposure to BP3 might affect other developmental stages of the mammary gland.