The metallohormone cadmium modulates AhR-associated gene expression in the small intestine of rats similar to ethinyl-estradiol

Abstract

Cadmium (Cd) affects the expression of estrogen receptor (ER) and aryl hydrocarbon receptor (AhR)-associated genes in rat uterus and elicits estrogen-like activity in vitro. The small intestine is highly exposed to dietary Cd which may mimic or antagonize estrogen action in this tissue. We investigated the effects of Cd and 17-alpha-ethinylestradiol (EE₂) on AhR-associated gene expression after oral exposure of ovariectomized female Wistar rats, and metallothionein (Mt1a) expression as a typical metal-response marker. Mt1a in the small intestine was strongly induced by co-treatment with CdCl₂ at 2 mg/kg b.wt (Cd 2) and 0.1 mg/kg b.wt EE2 than by the single compound (3-day gavage). The Cd 2-induced down-regulation of Cyp1a1, Gsta2, and Nqo1 mRNA was not antagonized by pure anti-estrogen (2.5 mg/kg b.wt ZK191703 s.c., ZK). Interestingly, the EE₂-induced down-regulation of Cyp1a1, Gsta2, and Nqo1 mRNA was antagonized by Cd 2 in vivo and in colon cancer cell lines (HT-29 and CaCo-2, treated 5 days with Cd 1 µM and/or E₂ 0.01 µM) with low or no ER-beta expression. Dose dependency was studied after Cd exposure with drinking water (5 and 50 ppm CdCl₂ equivalent to 0.4 and 4 mg/kg b.wt; Cd 0.4, Cd 4) for 28 days and EE₂ as reference. Intestinal Mt1a expression was dose dependently induced, while AhR target genes were down-regulated by Cd 0.4 similar to EE₂ and more pronounced than by Cd 4. We propose that Cd modulates intestinal AhR-associated gene expression similar to estrogens, but (contrary to its effects in uterus) via ER-independent and/or ER-beta-mediated mechanisms. Our new data suggest interference of Cd with estrogen and AhR signaling in the small intestine.

Does oral exposure to cadmium and lead mediate susceptibility to colitis? The dark-and-bright sides of heavy metals in gut ecology

“…Similarly, activation of the aryl hydrocarbon receptor (AhR) pathway (induced in colitis, along with Cyp1a1 ) ameliorates DSS-induced colitis in mice 30 31 . Other examples of the modulation of mucosal immune responses by environmental factors involve the AhR and the estrogen receptor 32 33 ; this reinforces evidence in favor of an estrogen-like role of Cd in the intestine 34 and related anti-inflammatory role in the gut 35 . There are abundant literature data on the protective role of Hmox1 in clinical and experimental colitis 36 37 38 and mechanisms might also involve Cd-induced protective autophagy 39 .…”

Ameliorative Effect of Grape Seed Proanthocyanidin Extract on Cadmium‐Induced Meiosis Inhibition During Oogenesis in Chicken Embryos

“…Furthermore, being a potent metallohormone, Cd is active in dramatically decreasing the expression of genes related to ovarian follicle development (Weng et al, 2014), mediating the membrane estrogen receptor GPR30 (Yu et al, 2010), and activating the ERa signaling pathway (Liu et al, 2008). These deleterious Cdinduced effects are due at least partially, to Cd disrupting or altering the functional enzymes, ion channels, transporters, and hormones related to such genes, receptors, or pathways (Thompson and Bannigan, 2008;Thevenod, 2009;Kluxen et al, 2013). However, meiosis is critical to the differentiation of germ cells undergoing the process of haploid cell generation and to set the foundation for sexual reproduction (Hunt and Hassold, 2008).…”

Study and Determination of Aryl Hydrocarbon Receptor with Some Trace Elements in Fuel Filling Station Workers

“…sources, such as car exhausts, tobacco smoke, and fossil fuel combustion [31]. Disruption of the AHR gene by Pb can affect the mutagenicity and .carcinogenicity of PAHs and 2, 3,7,8-tetrachlorodibenzo-p -dioxin (TCDD) [32]. A number of.…”