Alteration of Mammary Gland Development and Gene Expression by In Utero Exposure to Cadmium

Abstract

Environmental exposure to estrogens and estrogen like contaminants during early development is thought to contribute to the risk of developing breast cancer primarily due to an early onset of puberty; however, exposure during key developing windows may also influence the risk of developing the disease. The goal of this study was to ask whether in utero exposure to the metalloestrogen cadmium alters mammary gland development due to acceleration of puberty onset or to an effect on early development of the mammary gland. The results show that, in addition to advancing the onset of puberty, in utero exposure to the metalloestrogen cadmium altered mammary gland development prior to its effect on puberty onset. In utero exposure resulted in an expansion of the number of mammosphere-forming cells in the neonatal mammary gland and an increase in branching, epithelial cells, and density in the prepubertal mammary gland. In the postpubertal mammary gland, there was a further expansion of the mammary stem/progenitor cell population and overexpression of estrogen receptor-alpha (ERα) that was due to the overexpression and altered regulation of the ERα transcripts derived from exons O and OT in response to estradiol. These results suggest that in utero exposure to cadmium increases stem/progenitor cells, cell density, and expression of estrogen receptor-alpha that may contribute to the risk of developing breast cancer.

Time‐specific impact of trace metals on breast density of adolescent girls in Santiago, Chile

“…This important temporal relation was hypothesized to be induced by the metalloestrogens increasing the number of mammosphere-forming cells, epithelia cells, branch points, and ultimately, breast density before its effect on the hypothalamic-pituitary-gonadal axis. 40,41 While we did not find an association between cadmium and breast density, it may be that different metals have different WOS (e.g., in utero and pubertal) for human breast development.…”

Melatonin: A Molecule for Reducing Breast Cancer Risk

“…In Japanese women, elevated dietary intake of Cd has been associated with ER+ breast cancer [ 120 ]. Furthermore, it has recently been described that in utero exposure to Cd increases stem/progenitor cells, cell density, and expression of ERα, thereby constituting a risk factor for BC development [ 121 ]. There are, however, other studies that showed no association between urinary concentration of Cd and risk for development of BC [ 122 , 123 ].…”

Estrogen Effects on Wound Healing

“…The three major forms of estrogens in humans are estradiol, estrone, and estriol, with estradiol being the predominant form [ 31 , 32 , 33 , 34 , 35 ]. The ovary is the main source of estrogen in the premenopausal period, and granulosa cells are the key cells to produce estrogen [ 36 , 37 , 38 , 39 , 40 ].…”