Arsenic abrogates the estrogen-signaling pathway in the rat uterus

Abstract

BackgroundArsenic, a major pollutant of water as well as soil, is a known endocrine disruptor, and shows adverse effects on the female reproductive physiology. However, the exact molecular events leading to reproductive dysfunctions as a result of arsenic exposure are yet to be ascertained. This report evaluates the effect and mode of action of chronic oral arsenic exposure on the uterine physiology of mature female albino rats.MethodsThe effect of chronic oral exposure to arsenic at the dose of 4 microg/ml for 28 days was evaluated on adult female albino rats. Hematoxylin-eosin double staining method evaluated the changes in the histological architecture of the uterus. Circulating levels of gonadotropins and estradiol were assayed by enzyme-linked immunosorbent assay. Expression of the estrogen receptor and estrogen-induced genes was studied at the mRNA level by RT-PCR and at the protein level by immunohistochemistry and western blot analysis.ResultsSodium arsenite treatment decreased circulating levels of estradiol in a dose and time-dependent manner, along with decrease in the levels of both LH and FSH. Histological evaluation revealed degeneration of luminal epithelial cells and endometrial glands in response to arsenic treatment, along with reduction in thickness of the longitudinal muscle layer. Concomitantly, downregulation of estrogen receptor (ER alpha), the estrogen-responsive gene - vascular endothelial growth factor (VEGF), and G1 cell cycle proteins, cyclin D1 and CDK4, was also observed.ConclusionTogether, the results indicate that arsenic disrupted the circulating levels of gonadotropins and estradiol, led to degeneration of luminal epithelial, stromal and myometrial cells of the rat uterus and downregulated the downstream components of the estrogen signaling pathway. Since development and functional maintenance of the uterus is under the influence of estradiol, arsenic-induced structural degeneration may be attributed to the reduction in circulating estradiol levels. Downregulation of the estrogen receptor and estrogen-responsive genes in response to arsenic indicates a mechanism of suppression of female reproductive functions by an environmental toxicant that is contra-mechanistic to that of estrogen.

Prevention of arsenic-mediated reproductive toxicity in adult female rats by high protein diet

“…Arsenic toxicity is reported to jeopardize female reproductive functions in diverse ways (Akram et al, 2010;Chatterjee & Chatterji, 2010). This study demonstrates that strategic use of high dietary proteins in the forms of casein and pea may help in preventing arsenicinduced female reproductive toxicity to a significant extent.…”

“…The levels of E 2 , LH and FSH are reported to diminish in arsenic-intoxicated rats (Chattopadhyay & Ghosh, 2010). Disrupted circulating level of E 2 is held responsible for the gross histological alteration of the uterus; however, a recent study demonstrated that arsenic also disrupts the estrogen signaling pathway (Chatterjee & Chatterji, 2010). All these effects may be involved in imposing serious troubles in maintaining normal reproductive functions and pregnancy outcome.…”

“…The source of the ROS is not precisely known but repeated oxidation and reduction of arsenic during its metabolism possibly contribute. The deleterious effects of arsenic are believed to be mediated largely by exaggerated ROS generation that can lead to DNA damage (single-strand breaks; Kitchin, 2001) and contribute significantly to the induction of gonadal toxicity (Akram et al, 2010;Chatterjee & Chatterji, 2010). It has been demonstrated that arsenic-induced increased generation of ROS causes oxidative damage to the proteins involved in the estrogen signaling pathway, thus, disrupts estrogen signaling (Chatterjee & Chatterji, 2010).…”

“…Arsenic exposure poses a serious threat to the ovary, the main source of E 2 (Chatterjee & Chatterji, 2010;Chattopadhyay & Ghosh, 2010). The levels of E 2 , LH and FSH are reported to diminish in arsenic-intoxicated rats (Chattopadhyay & Ghosh, 2010).…”

Elevated Level of Prostate Specific Antigen Among Prostate Cancer Patients and High Prevalence in the Gangetic Zone of Bihar, India

“…Because of prostate epithelial cell sensitivity, As reportedly plays a potential role in prostate carcinogenesis. It interacts with estrogen receptor and activates the estrogen-regulated genes due to which estrogen-signalling pathway is abrogated (Chatterjee and Chatterji, 2010) thereby producing elevated level of estrogen. This in turn is associated with increased risk of CaP (Modugno et al, 2001).…”