Maternal and offspring toxicity but few sexually dimorphic behavioral alterations result from nonylphenol exposure

Abstract

Nonylphenol ethoxylates are used in the production of surfactants and are found in numerous manufactured substances. para-Nonylphenol (NP) is a suspected endocrine disruptor, exhibiting estrogen-like activity and might cause alterations with developmental exposure. To evaluate such effects, pregnant Sprague–Dawley rats consumed diets containing 0 (n = 11), 25 (n = 10), 500 (n = 10), or 2,000 (n = 9) ppm NP beginning on gestational day (GD) 7. At postnatal day (PND) 21, offspring continued on the same maternal diets until PND 77 and were evaluated for behavioral alterations (open-field activity at PNDs 22–24, 43–45, 64–66, play behavior at PND 35, running wheel activity at PND 63–77, flavored solution intake at PND 69–75). During pregnancy and lactation, dams in the 25-, 500-, and 2,000-ppm groups consumed 9 to 25% less food, which was associated with a 17% less weight gain during GDs 1 to 21 in dams of the 2,000-ppm group, although this effect was not statistically significant. Gestation duration, birth weight, sex ratio of live pups, and number of live or dead pups per litter did not differ between treatment groups. Offspring body weight and food consumption were decreased in the 2,000-ppm group beginning at PND 28; however, an effect of feed aversion could not be eliminated. Behavioral assessments of offspring indicated no consistent NP-related effects in open-field activity at PNDs 22–24, 43–45, and 65–67 nor in running wheel activity at PNDs 63–75. Play behavior at PND 35 and intake of a 0.3% saccharin-flavored solution at PNDs 69–71 did not differ with respect to treatment groups. However, intake of a 3% sodium-flavored solution at PNDs 73–75 was significantly increased in offspring of the 2,000-ppm group and intake of regular water during this same time was also significantly increased. These results indicate that developmental NP treatment results in maternal and offspring toxicity as evidenced by decreased food intake and weight gain. However, behavioral alterations were evident only in increased intake of a sodium solution.

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.