Cadmium Mimics Estrogen-Driven Cell Proliferation and Prolactin Secretion from Anterior Pituitary Cells

Abstract

Cadmium (Cd) is a heavy metal of considerable occupational and environmental concern affecting wildlife and human health. Recent studies indicate that Cd, like other heavy metals, can mimic effects of 17β-estradiol (E2) involving E2 receptor (ER) activation. Lactotrophs, the most abundant cell type in anterior pituitary gland, are the main target of E2, which stimulates cell proliferation and increases prolactin secretion through ERα. The aim of this work was to examine whether Cd at nanomolar concentrations can induce cell proliferation and prolactin release in anterior pituitary cells in culture and whether these effects are mediated through ERs. Here we show that 10 nM Cd was able to stimulate lactotroph proliferation in anterior pituitary cell cultures from female Wistar rats and also in GH3 lactosomatotroph cell line. Proliferation of somatotrophs and gonadotrophs were not affected by Cd exposure. Cd promoted cell cycle progression by increasing cyclins D1, D3 and c-fos expression. Cd enhanced prolactin synthesis and secretion. Cd E2-like effects were blocked by the pure ERs antagonist ICI 182,780 supporting that Cd acts through ERs. Further, both Cd and E2 augmented full-length ERαexpression and its 46 kDa-splicing variant. In addition, when co-incubated Cd was shown to interact with E2 by inducing ERα mRNA expression which indicates an additive effect between them. This study shows for the first time that Cd at nanomolar concentration displays xenoestrogenic activities by inducing cell growth and stimulating prolactin secretion from anterior pituitary cells in an ERs-dependent manner. Cd acting as a potent xenoestrogen can play a key role in the aetiology of different pathologies of the anterior pituitary and in estrogen-responsive tissues which represent considerable risk to human health.

In vivo xenoestrogenic actions of cadmium and arsenic in anterior pituitary and uterus

“…Here, we demonstrated that both toxicants stimulate cell proliferation, modify pituitary hormone secretion, and up-regulate E2-responsive genes. Our present data tally with previous results from our laboratory demonstrating that nanomolar Cd concentrations exert estrogenic activity in the anterior pituitary cells in culture and in lactosomatotroph GH3 cell line (Ronchetti et al 2013). Regarding iAs, its xenoestrogenic effects on this gland have not been reported yet.…”

“…Cd and iAs, at micromolar doses, have been shown to inhibit anterior pituitary secretion through feedback mechanisms or by directly affecting anterior pituitary cells (Lafuente & Esquifino 1999, Poliandri et al 2003, 2006, Sarkar et al 2003, Miler et al 2010, Ronchetti 2014. However, we previously showed that Cd at nanomolar concentrations exerts E2-like activities on these cells in culture (Ronchetti et al 2013). However, to date, iAs-mediated effects on the anterior pituitary gland have not been studied.…”

Benzene and 2-ethyl-phthalate induce proliferation in normal rat pituitary cells

“…Indeed, the estrogen receptor is involved also in stimulation of proliferation and transcription in pituitary cell lines [14, 36, 39, 45], mainly via the ERK pathway [16]. Current evidence demonstrates that disruptors call several additional pathways into play including the AhR–AIP–ARNT system [23].…”

Cadmium and Reproductive Health in Women: A Systematic Review of the Epidemiologic Evidence

“…The toxicological evidence with respect to cadmium’s effects on the reproductive system was recently reviewed [12–14]. Cadmium may interfere with hormonal functioning by binding at both the nuclear estrogen receptor [15] and G-protein coupled receptor 30 (GPR30) [16–18] and indirectly by P450 side-chain cleavage or through the low density lipoprotein receptor [19, 20] thus, cadmium may also be involved in the etiology of hormonally sensitive health outcomes and diseases. Experimentally, cadmium has shown effects on estrogenic activity [15, 21–24], including toxic effects to the ovary [21, 25–27].…”

“…Experimentally, cadmium has shown effects on estrogenic activity [15, 21–24], including toxic effects to the ovary [21, 25–27]. Together with estrogen, cadmium increased estrogen receptor alpha mRNA expression beyond either estrogen or cadmium alone [20]. Further, cadmium may contribute to disease processes by altering the balance of oxidative stress [28].…”