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.
Highlights
Arsenic, a major pollutant of water as well as soil, is a known endocrine disruptor, and shows adverse effects on the female reproductive physiology
Dose and time-dependent effect of arsenic on serum estradiol levels In order to determine the effect of arsenic on serum estradiol levels in female Sprague-Dawley rats, the optimum dose responsible for the changes and the minimum time required to initiate maximum changes were resolved by ELISA of serum estradiol
In this study we report the effects of inorganic arsenic on the estrogen signaling pathway in rats, along with concomitant alterations of the uterine morphology and proliferation, to unravel the putative mechanisms behind reproductive failures associated with arsenic exposure
Summary
A major pollutant of water as well as soil, is a known endocrine disruptor, and shows adverse effects on the female reproductive physiology. This report evaluates the effect and mode of action of chronic oral arsenic exposure on the uterine physiology of mature female albino rats. Arsenic is a naturally occurring metalloid with potent toxic and mutagenic effects [1]. It is present ubiquitously in the environment and is released from both natural and man-made sources [2]. It has been reported that there is an increased risk of arsenic toxicity, even at the low and permissible dose of 10 ppb [9,15,16,17]. Arsenic is not a direct acting xenotoxin or mutagen, it may increase DNA damage or mutations indirectly by altering DNA repair, acting as a co-carcinogen or promoter of tumor growth [25]
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