Prepubertal exposure to elevated manganese results in estradiol regulated mammary gland ductal differentiation and hyperplasia in female rats

Abstract

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 (E2). 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 E2 driven pathways involved in tumorigenesis. Sprague Dawley female rats were gavaged daily with either 10 mg/kg manganese chloride (MnCl2) 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 E2 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.

Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases

“…Manganese, which is found in various industrial processes and products, exposure can occur through inhalation, oral, dermal, and occupational routes. Recently, prepubertal exposure to environmental levels of Mn has been shown to produce precocious mammary gland development through inducing gonadotropin-releasing hormone (GnRH) regulated increases in levels of serum LH and E2 by activating the hypothalamic-pituitary-ovarian axis [173]. MnCl2 (1.0 µM) is almost 9% as efficient as 17-β estradiol in activating estrogen receptor-mediated transcriptional activity in MCF-7 breast cancer cells.…”

“…MnCl2 (1.0 µM) is almost 9% as efficient as 17-β estradiol in activating estrogen receptor-mediated transcriptional activity in MCF-7 breast cancer cells. Mn has been show to accumulate in the hypothalamus and induces precocious puberty in rats through activating GnRH peptide release from the basal hypothalamus leading to elevated puberty-related hormones including E2 [173]. …”

“…However, PCBs, BPA, phthalates, Cd, As or Mn, through influencing gonadotropin-releasing hormone (GnRH) regulated increases in levels of serum LH and E2, have been shown to modify the hypothalamic–pituitary-ovarian axis and they also bind to estrogen receptors [1,2,149,173]. BPA, Phthalates and metalloestrogens—Cd, As and Mn have been shown to cross the blood brain barrier [1,64,65,118,119,149,173]. Metalloestrogens, such as arsenite, cadmium, mimic the actions of physiological estrogens through binding to estrogen receptors [196,197,198].…”

Manganese and the Insulin-IGF Signaling Network in Huntington’s Disease and Other Neurodegenerative Disorders

“…These results were consistent with reports that diabetic patients were responsive to oral Mn treatment as well as reports of reduced blood Mn in diabetic patients 72–74 . Concurrently, other groups established that Mn deficiency was associated with reductions of IGF1 in serum and Mn supplementation could increase IGR-R and IGF1 expression in the hypothalamus of rats 53, 54, 56, 70, 75–78 However, the mechanisms bv which Mn increases IGF1 and insulin levels remain unknown. Together, these findings suggest a functional link between Mn and the regulation of IGFl/insulin levels in both peripheral tissues and brain.…”

Modeling estrogen receptor-positive breast cancers in mice: is it the best we can do?

“…As can readily be seen, the laboratory mouse is really a poor choice since E2 levels in all of these animals exceed considerably those of the common laboratory mice and range within levels that occasionally approach and exceed the minimal levels reported in women. Similarly low E2 levels are also present in the rat, another species used to model breast cancer (Dearth et al, 2014; Rumi et al, 2014; Ström et al, 2008). The fact that almost half of the ER-positive breast cancers develop in post-menopausal women, at which E2 levels decrease, strongly supports the hypothesis that ER-positive breast cancers may grow in animals bearing even moderately higher E2 levels than those of mice.…”