Histopathologic changes in the uterus, cervix and vagina of immature CD-1 mice exposed to low doses of perfluorooctanoic acid (PFOA) in a uterotrophic assay

Abstract

The estrogenic and antiestrogenic potential of perfluorooctanoic acid (PFOA) was assessed using an immature mouse uterotrophic assay and by histologic evaluation of the uterus, cervix and vagina following treatment. Female offspring of CD-1 dams were weaned at 18 days old and assigned to groups of equal weight, and received 0, 0.01, 0.1, or 1 mg PFOA/kg BW/d by gavage with or without 17-β estradiol (E 2 , 500 μg/kg/d) from PND18-20 (n=8/treatment/block). At 24 hr after the third dose (PND 21), uteri were removed and weighed. Absolute and relative uterine weights were significantly increased in the 0.01 mg/kg PFOA only group. Characteristic estrogenic changes were present in all E 2 -treated mice; however, they were minimally visible in Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of interestAll authors declare there are no financial conflict of interest issues. DisclaimerThe information in this document has been subjected to review by the National Institute of Environmental Health Sciences, NIH and the U.S. EPA's National Health and Environmental Effects Laboratory and approved for publication. This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH or the United States government. NIH Public Access

Comparative in vivo and in vitro analysis of possible estrogenic effects of perfluorooctanoic acid

“…These investigators also provided evidence supporting the hypothesis that activation of ER mediated these PFOA-dependent effects in the reproductive tract (Dixon et al, 2012). However, although immature female CD-1 mice were exposed to three different doses of PFOA (0.01, 0.1 and 1.0 mg/kg), these effects were only observed at the lowest dose of PFOA (0.01 mg/kg) and no dosedependent effects were noted (Dixon et al, 2012). Thus, the present studies further examined the hypothesis that low dose PFOA exposure comparable to that found in humans causes ERdependent changes using an in vivo uterotrophic assay and an in vitro reporter assay.…”

“…It was recently shown that low-dose exposure to PFOA during early postnatal development caused estrogenic-like activities in immature female CD-1 mice as shown by differences observed in the reproductive tract (Dixon et al, 2012). However, these effects were not observed in a dose-dependent fashion, and the authors hypothesized an inverted-U shaped dose response to explain these effects observed in a single dose group (0.01 mg PFOA/kg), but not the others (0.1 or 1.0 mg PFOA/kg) (Dixon et al, 2012).…”

“…However, two recent cross-sectional epidemiological studies suggest an association between fetal exposure to PFOA and a delay of menarche, and/or a longer menstrual cycles in humans (Kristensen et al, 2013;Lyngso et al, 2014), suggesting that the female reproductive system may be sensitive to PFOA exposure. Since most studies showing effects modulated by activation of ER that could potentially influence the female reproductive tract use concentrations of PFOA that exceed those found in humans, it is of particular interest to note that a recent study showed that low dose PFOA caused changes in uterine histology in immature female CD-1 mice (Dixon et al, 2012). These investigators also provided evidence supporting the hypothesis that activation of ER mediated these PFOA-dependent effects in the reproductive tract (Dixon et al, 2012).…”

“…Since most studies showing effects modulated by activation of ER that could potentially influence the female reproductive tract use concentrations of PFOA that exceed those found in humans, it is of particular interest to note that a recent study showed that low dose PFOA caused changes in uterine histology in immature female CD-1 mice (Dixon et al, 2012). These investigators also provided evidence supporting the hypothesis that activation of ER mediated these PFOA-dependent effects in the reproductive tract (Dixon et al, 2012). However, although immature female CD-1 mice were exposed to three different doses of PFOA (0.01, 0.1 and 1.0 mg/kg), these effects were only observed at the lowest dose of PFOA (0.01 mg/kg) and no dosedependent effects were noted (Dixon et al, 2012).…”

Role of Environmental Factors and Gonadotoxin Exposure in Unexplained Female Infertility

“…Experimental studies in mice have reported altered estrous cyclicity following PFOS treatment [160], and dosedependent increases in total litter resorption following PFOA treatment [161], albeit at levels exceeding those typically experienced by women. Additional studies suggest PFOS and PFOA possess estrogenic and antiestrogenic activities [162,163]. No adverse reproductive effects were detected at nontoxic PFOS doses in an earlier two-generation rat study [164] although these results were limited by rapid metabolism and elimination of perfluorinated compounds by the female rat, whereas the elimination half-life in humans is measured in years.…”