Dearth Robert K, Hiney Jill K, Srivastava Vinod K, Hamilton Alina M, Dees William L
Department of Biology, College of Science and Mathematics, University of Texas-Pan American, Edinburg, TX 78539, USA
Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4458, USA.
Exp Biol Med (Maywood). 2014 Jul;239(7):871-882. doi: 10.1177/1535370214531865. Epub 2014 May 20.
Evidence suggests that environmental substances regulating estrogenic pathways during puberty may be detrimental to the developing mammary gland (MG). Manganese (Mn) is a trace mineral required for normal physiological processes. Prepubertal exposure to Mn induces precocious puberty in rats, an event associated with early elevations in puberty-related hormones, including estradiol (E). However, until now the effect of Mn-induced precocious MG development has not been determined. Therefore, we assessed the ability of prepubertal Mn exposure to advance normal MG development and alter E driven pathways involved in tumorigenesis. Sprague Dawley female rats were gavaged daily with either 10 mg/kg manganese chloride (MnCl) or saline (control) from postnatal day (PND) 12 through PND 30. Blood and MGs were collected on PNDs 30 and 120. Compared to controls, serum E levels on PND 30 were elevated (p < 0.05) in the Mn-treated group. Mn exposure significantly increased differentiated MG terminal ductal structures and the percentage of MG epithelial cells that stained positive for the proliferative marker, Ki67, at PND 30 (p < 0.001) and PND 120 (p < 0.001). Levels of Mn (ppm) were not elevated in these MGs. Mn-treated animals (40%) exhibited reactive stroma and intra-luminal focal hyperplasia in hemotoxylin and eosin stained MGs at PND 120. Furthermore, Mn exposure resulted in elevated protein expression levels of estrogen receptor α, activator protein 2α, phosphorylated (p)-Akt, and p53 in MGs on PND 120, but not on PND 30. Collectively, these data show that exposure to a supplemental dose of Mn causes accelerated pubertal MG growth which can progress to adult hyperplasia; thus, providing evidence that early life Mn exposure may increase susceptibility to breast cancer.
有证据表明，青春期期间调节雌激素途径的环境物质可能对发育中的乳腺（MG）有害。锰（Mn）是正常生理过程所需的一种微量矿物质。青春期前接触锰会诱导大鼠性早熟，这一事件与青春期相关激素（包括雌二醇（E））的早期升高有关。然而，到目前为止，锰诱导的乳腺早熟发育的影响尚未确定。因此，我们评估了青春期前接触锰促进正常乳腺发育以及改变参与肿瘤发生的雌激素驱动途径的能力。从出生后第12天（PND）到第30天，每天给斯普拉格-道利雌性大鼠灌胃10mg/kg氯化锰（MnCl）或生理盐水（对照）。在PND 30和120收集血液和乳腺。与对照组相比，锰处理组在PND 30时血清E水平升高（p<0.05）。在PND 30（p<0.001）和PND 120（p<0.001）时，接触锰显著增加了分化的乳腺终末导管结构以及增殖标志物Ki67染色阳性的乳腺上皮细胞百分比。这些乳腺中的锰（ppm）水平没有升高。在PND 120时，锰处理的动物（40%）在苏木精和伊红染色的乳腺中表现出反应性间质和管腔内局灶性增生。此外，接触锰导致PND 120时乳腺中雌激素受体α、激活蛋白2α、磷酸化（p）-Akt和p53的蛋白表达水平升高，但在PND 30时没有升高。总体而言，这些数据表明，接触补充剂量的锰会导致青春期乳腺生长加速，并可能发展为成年期增生；因此，提供了早期接触锰可能增加患乳腺癌易感性的证据。
