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.
Highlights
Cadmium (Cd) is a heavy metal that is dispersed throughout the environment mainly as a result of pollution from industrial and agricultural practices [1,2]
Cadmium stimulates anterior pituitary cell proliferation Many authors have reported that E2 stimulates anterior pituitary cell proliferation
To determine whether Cd affects proliferation of these cells, primary cultures of anterior pituitary cells were incubated with increasing concentrations of Cd ranging from 10-12 M to 10-6 M for 96 h
Summary
Cadmium (Cd) is a heavy metal that is dispersed throughout the environment mainly as a result of pollution from industrial and agricultural practices [1,2]. Asides from occupational exposure, human intoxication results from consumption of contaminated water and food or inhalation of cigarette smoke [3]. Since Cd can not be degraded, the risk of environmental exposure and contamination is constantly increasing because of accumulation via both water and the food chain [2] and Cd long half-life (over 26 years) in the whole body in humans. Endocrine disrupting chemicals (EDCs) are natural or synthetic compounds that interfere in the biosynthesis, metabolism or action of endogenous hormones. Many chemicals in the environment can act as endocrine active compounds [5]. Several reports show that Cd possesses estrogen-like activity [6,7,8,9]. Cd has been shown to have potent estrogen- and androgenlike activities in vivo and in vitro by directly binding to estrogen and androgen receptors [10,11,12]
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