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Effects of Developmental Exposure to Bisphenol A on Spatial Navigational Learning and Memory in Rats: A CLARITY-BPA Study

Sarah A. Johnson, Angela B. Javurek, Michele S. Painter, Mark R. Ellersieck, Thomas H. Welsh, Jr., Luísa Camacho, Sherry M. Lewis, Michelle M. Vanlandingham, Sherry A. Ferguson, and Cheryl S. Rosenfeld.
Hormones and Behavior (2016) DOI: PMID: 26436835



Bisphenol A (BPA) is a ubiquitous industrial chemical used in the production of a wide variety of items. Previous studies suggest BPA exposure may result in neuro-disruptive effects; however, data are inconsistent across animal and human studies. As part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA), we sought to determine whether female and male rats developmentally exposed to BPA demonstrated later spatial navigational learning and memory deficits. Pregnant NCTR Sprague-Dawley rats were orally dosed from gestational day 6 to parturition, and offspring were directly orally dosed until weaning (postnatal day 21). Treatment groups included a vehicle control, three BPA doses (2.5μg/kg body weight (bw)/day-[2.5], 25μg/kg bw/day-[25], and 2500μg/kg bw/day-[2500]) and a 0.5μg/kg/day ethinyl estradiol (EE)-reference estrogen dose. At adulthood, 1/sex/litter was tested for seven days in the Barnes maze. The 2500 BPA group sniffed more incorrect holes on day 7 than those in the control, 2.5 BPA, and EE groups. The 2500 BPA females were less likely than control females to locate the escape box in the allotted time (p value=0.04). Although 2.5 BPA females exhibited a prolonged latency, the effect did not reach significance (p value=0.06), whereas 2.5 BPA males showed improved latency compared to control males (p value=0.04), although the significance of this result is uncertain. No differences in serum testosterone concentration were detected in any male or female treatment groups. Current findings suggest developmental exposure of rats to BPA may disrupt aspects of spatial navigational learning and memory.


Figure 1. Total distance traveled, velocity, and incidence of sniffing incorrect holes for females and males combined in each treatment group.

A) Total distance traveled (mm) (mean ± SEM). Comparisons of the significant treatment ∗ day interaction indicated that on day 2, EE animals traveled less distance than controls and all treatment groups (p range = 0.01 to 0.05, asterisk). On day 5, EE animals traveled more distance than those in the 2500 BPA group (p = 0.03, delineated by the bracketed line). On day 7, 2.5 BPA animals traveled less distance than 2500 BPA animals (p = 0.003, delineated by the bracketed line).
B) Velocity (mm/s) (mean ± SEM). There were no significant effects detected in the analysis of velocity.
C) Incidence of sniffing incorrect holes. Comparisons of the significant treatment ∗ day interaction indicated that on day 2, EE animals sniffed fewer incorrect holes than controls and all other treatment groups (p range = 0.002 to 0.01). On day 5, however, EE animals sniffed more incorrect holes than those in the 2.5 and 2500 BPA groups (p range = 0.001 to 0.04, delineated by bracketed lines). On the last trial day, animals in the 2500 BPA group sniffed more incorrect holes than those in the control, 2.5 BPA, and EE groups (p range = 0.007 to 0.05, delineated by bracketed lines).

Figure 2. Overall ratio for females and males in each treatment group to locate the escape hole.

Note that increasing indicates shorter latency. For both panels, the upper, middle, and lower bars represent the ratio of locating the correct escape hole at the 95% upper confidence limit, mean, and 95% lower confidence limit, respectively, for each group. Comparisons of the significant two-way interaction for treatment ∗ sex are shown.
A) Overall ratio for females. B) Overall ratio for males.

Figure 3. Comparisons of the use of the efficient direct search strategy versus the inefficient search strategies (random and serial) for females (Panel A) and males (Panel B).

Yellow = Probability of using an inefficient search strategy (random or serial). Green = Probability of using the direct search strategy. There were no significant effects involving treatment. Thus, while latency (or percent likelihood) differed by treatment and sex, females and males employed the inefficient and direct search strategies at comparable percentages.

Figure 4. Adult serum testosterone concentrations (mean ± SEM) in females (A) and males (B).

There are no differences in serum testosterone concentrations between any of the female or male treatment groups.

Supplemental Materials

Supplementary Data

Table S1. Criteria for exclusion of individual sessions.

Table S2. Number of replicates per treatment group for serum testosterone concentration measurements and those that were below the limit of detection (BLD).

Figure S1. A schematic of the Barnes maze test room. This view faces the east side of the room. The 3 black visual stimuli are shown against the white walls: horizontal stripe, two vertical stripes, and large circle above the door. The Barnes maze is shown, as well as other dimensions.

Figure S2. Incidences of sniffing incorrect holes for females and males combined across treatment groups. On day 3, females sniffed more incorrect holes than males (p = 0.02, *).

Figure S3. Comparison of inefficient versus direct search strategy for all animals. Comparisons of the significant main effect of day indicated the direct search strategy was employed more on day 7 than days 1 and 2 (p range = 0.04 to 0.05).