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Impact of Low-Dose Oral Exposure to Bisphenol A (BPA) on Juvenile and Adult Rat Exploratory and Anxiety Behavior: A CLARITY-BPA Consortium Study

Meghan E. Rebuli, Luísa Camacho, Maria E. Adonay, David M. Reif, David L. Aylor, and Heather B. Patisaul.
Toxicological Sciences (2015) DOI: https://doi.org/10.1093/toxsci/kfv163 PMID: 26209558


Publication


Abstract

Bisphenol A (BPA) is a high volume production chemical and has been identified as an endocrine disruptor, prompting concern that developmental exposure could impact brain development and behavior. Rodent and human studies suggest that early life BPA exposure may result in an anxious, hyperactive phenotype but results are conflicting and data from studies using multiple doses below the no-observed-adverse-effect level are limited. To address this, the present studies were conducted as part of the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) program. The impact of perinatal BPA exposure (2.5, 25, or 2500 µg/kg body weight (bw)/day) on behaviors related to anxiety and exploratory activity was assessed in juvenile (prepubertal) and adult NCTR Sprague-Dawley rats of both sexes. Ethinyl estradiol (0.5 µg/kg bw/day) was used as a reference estrogen. Exposure spanned gestation and lactation with dams gavaged from gestational day 6 until birth and then the offspring gavaged directly through weaning (n = 12/sex/group). Behavioral assessments included open field, elevated plus maze, and zero maze. Anticipated sex differences in behavior were statistically identified or suggested in most cases. No consistent effects of BPA were observed for any endpoint, in either sex, at either age compared to vehicle controls; however, significant differences between BPA-exposed and ethinyl estradiol-exposed groups were identified for some endpoints. Limitations of this study are discussed and include suboptimal statistical power and low concordance across behavioral tasks. These data do not indicate BPA-related effects on anxiety or exploratory activity in these developmentally exposed rats.

Figures


Figure 1. Methods timeline.

Visual depiction of the experimental methods timeline including dosing and housing. Dam and pup gavages occurred in the core animal facility (white arrows), and the experimental animals were transferred to a different animal facility on postnatal day (PND) 21 and acclimated to the new facility from PND 21 to 25 for subsequent testing. Juveniles (gray arrow) were tested prior to puberty. Adults were tested in 2 groups (black arrows) and the time of behavioral testing for each group is indicated.

Figure 2. Juvenile elevated plus maze (EPM).

A, ANOVA P-values for main effects of exposure, sex, and their interaction for each endpoint. Significant effects are bolded and highlighted in gray and the direction of significant sex differences is indicated (M = male; F = female).
B, Time in the open arms did not differ by sex or across exposure groups.
C, Number of stretch attends was sexually dimorphic, with females performing more stretch attends than males. This sex difference was not statistically significant in the vehicle controls or the bisphenol A (BPA) 2.5 groups. No effects of ethinyl estradiol (EE) or BPA were observed versus vehicle control. Distance traveled on the open arms D, and number of open arm entries E, were not impacted by sex or exposure. Graphs depict mean ± SEM. For all graphs, females are depicted in open bars and males in striped bars. Sex differences within exposure group are indicated by &P ≤ .05 and &&P ≤ .01.

Figure 3. Juvenile OF.

A, ANOVA P-values for main effects of exposure, sex, their interaction, and test day for each endpoint. Significant effects are bolded and highlighted in gray. Sex and test day differences are indicated (M = male; F = female; 1 = first test day; 2 = second test day). Distance traveled B, entries into the center C, and time in the center D, differed by sex but did not differ across exposure groups. No effects of ethinyl estradiol (EE) or bisphenol A (BPA) were observed versus vehicle control. Graphs depict mean ± SEM. For all graphs, females are represented by open shapes and males by black, filled shapes. Each interval was 5 min; all graphs show results from the first day of testing (data from the second day are not shown). Main effect of sex denoted by &P ≤ .05 and &&P ≤ .01.

Figure 4. Adult elevated plus maze (EPM).

A, ANOVA P-values for main effects of exposure, sex, and their interaction for each endpoint. Significant effects are bolded and highlighted in gray. Sex and group differences are indicated (M = male; F = female). B, Time in the open arms differed by exposure and sex. The ethinyl estradiol (EE) group had a significantly longer time on the open arms than the vehicle group. Bisphenol A (BPA) 2.5 and 2500 groups differed significantly from the ethinyl estradiol (EE) group, but not the vehicle controls. Sex differences were identified in the BPA 2.5 and 25 groups, but not in the vehicle controls. C, Number of stretch attends was not impacted by sex or exposure. D, Distance traveled in the open arms was sexually dimorphic with females traveling farther. E, Open arm entries were not impacted by exposure but were sexually dimorphic. This sex difference was only statistically significant in the BPA 2.5 group. Graphs depict mean ± SEM. For all graphs, females are depicted in open bars and males in striped bars. Group differences compared to the vehicle control group are indicated with *P ≤ .05. Sex differences within exposure group are indicated by &P ≤ .05; &&P ≤ .01; and &&&P ≤ .001.

Figure 5. Adult OF.

A, ANOVA P-values for main effects of exposure, sex, their interaction, and test day for each endpoint. Significant effects are bolded and highlighted in gray. Sex and test day differences are indicated (M = male; F = female; 1 = first test day; 2 = second test day). Distance traveled B, entries into the center C, and time in the center D, differed by sex, but did not differ across exposure groups. No effects of ethinyl estradiol (EE) or bisphenol A (BPA) were observed. Graphs depict mean ± SEM. For all graphs, females are represented by open shapes and males by black, filled shapes. Each interval was 5 min; all graphs show results from the first day of testing (data from the second day are not shown). Main effect of sex denoted by && P ≤ .01 and &&&P ≤ .001.

Figure 6. Adult ZM.

A, ANOVA P-values for main effects of exposure, sex, and their interaction for each endpoint. Significant effects are bolded and highlighted in gray. Sex and group differences are indicated (M = male; F = female). B, Time in the open arms was not impacted by sex or exposure group. C, Number of stretch attends was sexually dimorphic with females performing fewer stretch attends. No effects of ethinyl estradiol (EE) or bisphenol A (BPA) were identified. D, Distance traveled in the open arms was not impacted by sex or exposure group. Graphs depict mean ± SEM. For all graphs, females are depicted in open bars and males in striped bars. Sex differences within exposure group are indicated by &&P ≤ .01.

Supplemental Materials


Supplementary Data