ArticlesMaternal and offspring toxicity but few sexually dimorphic behavioral alterations result from nonylphenol exposure
Introduction
A variety of adverse effects (e.g., decreased sperm counts in men, reproductive impairments in wildlife) are proposed to be the result of exposure to environmental compounds that modulate endocrine functions. Relevant to such environmental exposure, several reviews have outlined the environmental and health concerns, reviewed existing data, and evaluated research needs 4, 15, 22, 39, 40. Much of the concern appears focused on those compounds with estrogenic and/or androgenic actions [35] and the highest priority for risk assessment appears to be research on developmental exposure to such compounds.
Concern about exposure to environmental estrogen and/or androgen exposures may be well founded given the results of laboratory research on exogenous treatment with steroid hormones. Developmental estrogen or androgen treatment can result in alterations of sexually dimorphic rodent behaviors such as maze performance 5, 38, operant response extinction [31], open-field activity 1, 37, 45, play behavior 29, 42, salt intake [16], and sexual behavior 3, 43, 46. Such differences induced by developmental hormone treatment likely alter the normal hormonally influenced pattern of organizational effects.
A recent review focused attention on the alkylphenol ethoxylates of which nonylphenol ethoxylates are the most common [26]. Nonylphenol ethoxylates are used as an industrial intermediate in the production of surfactants and are found in latex coatings and adhesives, paper and pulp production, textile manufacture and dyeing, agricultural chemicals, institutional cleaners, cosmetics, and spermicides [24]. para-Nonylphenol (NP) became a suspect endocrine disruptor due to its estrogenic effects. NP has been shown to bind to estrogen receptors 10, 33, 44, promote the proliferation of MCF-7 cells 36, 44, induce rat uterine mitotic activity [36], increase uterine weight gain in rats and mice 21, 33, and accelerate vaginal opening [2]. Both developmental and adult NP treatment produce alterations in the male reproductive tract, such as decreased testicular and epididymal mass and decreased sperm count 6, 7. Such alterations may be related to impaired fertility [20]. NP is a weak estrogen relative to estradiol (reviewed in Muller et al. [23]) and, in addition to its estrogenic effects, NP also appears to be a weak androgen agonist [34]. Daily oral intake of NP has been estimated to be 0.16 mg/day [23].
Increasing evidence for the estrogenic and/or androgenic nature of NP and the sensitivity of rodent sexually dimorphic behaviors to disruption by exogenous hormone treatment provide compelling reasons for further investigation of the effects of developmental NP treatment. In particular, the effects of developmental NP treatment on neurobehavioral functions have not been described. Here, beginning on gestational day (GD) 7, NP was mixed in the food of pregnant rats at levels of 0, 25, 500, or 2,000 ppm. Offspring continued on the same diets throughout the study. In addition to body weight and food intake, four behaviors were assessed in male and female offspring: open-field activity, running wheel activity, juvenile play behavior, and intake of sodium- and saccharin-flavored solutions.
Section snippets
Animals
Forty-eight date-mated primiparous Sprague-Dawley rats were obtained from the National Center for Toxicological Research (NCTR) breeding colony (sperm plug date is GD 0) after breeding with males maintained on normal NIH-31 diets. Each dam was housed individually in a standard polycarbonate tub cage lined with wood chip bedding. Food and water were provided ad libitum. The housing room was maintained on a 12:12-h light-dark cycle, temperature was maintained at 23 ± 3°C, and humidity at 50 ±
Dams and litters
Eight sperm-plug-positive dams were not pregnant (two in the 0-ppm group, three in the 25-ppm group, two in the 500-ppm group, and one in the 2,000-ppm group); their data are not included in any analyses. Five dams delivered on GD 21 (three in the 25-ppm group, one in the 500-ppm group, and one in the 2,000-ppm group); thus, their data are not included in the weight gain analyses. However, there were no significant effects of NP exposure on gestation duration or dam body weight during pregnancy
Discussion
Developmental and lifelong exposure to NP resulted in significant decrements in body weight and food consumption of dams and/or offspring, but had little effect on most of the assessed behaviors. Although not statistically significant, dams in the 2,000-ppm group gained less weight during pregnancy; however, body weights of their male and female offspring were significantly decreased in weight beginning shortly after weaning. The same offspring (2,000 ppm) exhibited a significantly increased
Acknowledgements
This study was funded under Interagency Agreement no. 224-93-0001 between the National Institute of Environmental Health Sciences and the U.S. Food and Drug Administration. K.M.F was supported by an appointment to the Postgraduate Research Program at the National Center for Toxicological Research administered by the Oak Ridge Institute for Science and Education through an Interagency Agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. The authors express
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2014, Environmental ResearchCitation Excerpt :Notably, estrogen production plays an important role in promoting the expression of critical growth factors for placental villous angiogenesis and in regulating the processes of growth and development in the fetus (Albrecht and Pepe, 2010; Fujimoto et al., 2005). The adverse effects of NP include inhibition of gonadal development, low testis and epididymis mass, inhibition of ovarian development, and reduction in offspring viability (De Jager et al., 1999; Fan et al., 2001; Ferguson et al., 2000; Harris et al., 2001; Holdway et al., 2008; Jie et al., 2010; LeBlanc et al., 2000; Nagao et al., 2001; Yokota et al., 2001). NP exposure in utero may influence the weight of the infant׳s body and some reproductive organs, possibly inducing neurotoxic and reproductive toxic effects in the offspring (Kimura et al., 2006).