BMC Cancer, 2014, 14(1):379-379.

Cell proliferation and apoptosis in rat mammary glands following combinational exposure to bisphenol A and genistein

Jun Wang, Sarah Jenkins, Coral A Lamartiniere

Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA

BACKGROUND:

Humans are exposed to an array of both harmful and beneficial hormonally active compounds in the environment and through diet. Two such chemicals are Bisphenol A (BPA), a plasticizer, and genistein, a component of soy. Prepubertal exposure to BPA increased mammary carcinogenesis, while genistein suppressed cancer in a chemically-induced model of rodent mammary cancer. The purpose of this research was to determine the effects of combinational exposure to genistein and BPA on cell proliferation, apoptosis, and associated proteins as markers of cancer in mammary glands of rats exposed prepubertally to these environmental chemicals.

METHODS:

Prepubertal rats (postpartum days (PND) 2-20) were exposed through lactation via nursing dams treated orally with sesame oil (SO), BPA, genistein, or a combination of BPA and genistein (BPA + Gen). Cell proliferation, apoptosis and protein expressions were investigated for mechanistic studies in mammary glands of rats exposed to these environmental chemicals.

RESULTS:

Prepubertal exposure to genistein increased cell proliferation in mammary glands of PND21 rats, while BPA increased cell proliferation in adult (PND50) rats. Prepubertal combinational exposure to BPA + Gen increased cell proliferation and reduced apoptosis in PND21 rats, but reduced cell proliferation and increased apoptosis in PND50 rats. The altered mechanisms behind these cellular responses appear to be centered on differential protein expression of caspases, PARP, Bad, p21, Akts, PTEN, ER-β and SRCs 1-3, in the rat mammary gland.

CONCLUSION:

Prepubertal BPA exposure resulted in increased cell proliferation in mammary glands of PND50 rats, a process associated with increased risk of cancer development in a chemically-induced mammary cancer. On the other hand, genistein stimulated cell proliferation at PND21, a process that correlates with mammary gland maturation and chemoprevention. In contrast to single chemical exposure, combinational exposure to BPA + Gen performed most similarly to genistein exposure alone. BPA + Gen increased cell proliferation at PND21, suggesting mammary gland maturation, and decreased cell proliferation while increasing apoptosis in PND50 rats, suggesting mammary chemoprevention. Differential expression of proteins involved in regulating cell proliferation and apoptosis lend support to these chemicals, both alone and in combination, altering mammary gland cancer susceptibility.

英国《BMC癌症》，2014年5月

在双酚 A 和金雀异黄素联合治疗之后大鼠乳腺中的细胞增殖和细胞凋亡

王俊、 莎拉 詹金斯、 卡洛儿 A 拉马蒂尼埃

美国阿拉巴马大学伯明翰分校药理学和毒理学学院和UAB 综合癌症中心

背景︰

在生活中人体通过饮食接触到大量有害和有益的激素活性化合物。这两种化学物质是双酚 A (BPA)，一种 增塑剂， 和金雀异黄素， 大豆的一种组成部分。在化学诱导乳腺肿瘤的啮齿动物模型中青春期前接触双酚 A 增加乳腺的癌变过程，而金雀异黄素会抑制癌症。本研究的目的是确定对于青春期前接触化学药品的大鼠，组合接触金雀异黄素和双酚 A对细胞增殖、 凋亡及与肿瘤标记相关的蛋白质的影响。

方法︰

青春期前大鼠 （出生后天数 (PND) 2-20）通过哺乳护理疗法口服芝麻油SO、 双酚 A、 金雀异黄素或双酚 A 和金雀异黄素 （BPA + Gen） 的组合物。在接触这些化学试剂的大鼠乳腺组织中细胞增殖、 凋亡和蛋白表达被用于机理研究。

结果︰

青春期前接触金雀异黄素增加了 PND21 大鼠乳腺组织细胞的增殖，而双酚 A 增加成年 (PND50) 大鼠的细胞增殖。青春期前接触组合物BPA + Gen促进了PND21 大鼠细胞增殖并减少了细胞凋亡，但是减少了PND50 大鼠的细胞增殖，促进细胞凋亡。这些细胞响应背后的蚀变机制集中出现在大鼠乳腺组织半胱氨酸蛋白酶，PARP，Bad，p21，Akts， PTEN， ER-β 和SRCs1-3的差异性蛋白表达中。

结论︰

青春期前接触双酚 A 导致PND50 大鼠的乳腺组织细胞增殖增加，这一进程与化学诱导细胞癌变的乳腺癌风险增加有关。另一方面，金雀异黄素刺激PND21的细胞增殖，这一过程与乳腺组织成熟和化学预防相关。与接触单一化学试剂相比，接触组合物双酚 A + Gen的表现与单独接触金雀异黄素最相似。BPA + Gen促进了PND21的细胞增殖，表明乳腺组织成熟，并且当促进 PND50 大鼠细胞凋亡时降低细胞增殖，表明乳腺化学预防。调节细胞增殖和凋亡的蛋白质的差异性表达表明这些化学药品，单独和组合，可以改变乳腺肿瘤的易感性。