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Effects of Perinatal Bisphenol A Exposure on the Volume of Sexually-dimorphic Nuclei of Juvenile Rats: A CLARITY-BPA Consortium Study

Sheryl E. Arambula, Joelle Fuchs, Jinyan Cao, and Heather B. Patisaul.
NeuroToxicology (2017) DOI: https://doi.org/10.1016/j.neuro.2017.09.002 PMID: 28890130

Publication

Abstract

Bisphenol A (BPA) is a high volume endocrine disrupting chemical found in a wide variety of products including plastics and epoxy resins. Human exposure is nearly ubiquitous, and higher in children than adults. Because BPA has been reported to interfere with sex steroid hormone signaling, there is concern that developmental exposure, even at levels below the current FDA No Observed Adverse Effect Level (NOAEL) of 5mg/kg body weight (bw)/day, can disrupt brain sexual differentiation. The current studies were conducted as part of the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) program and tested the hypothesis that perinatal BPA exposure would induce morphological changes in hormone sensitive, sexually dimorphic brain regions. Sprague-Dawley rats were randomly assigned to 5 groups: BPA (2.5, 25, or 2500μg/kgbw/day), a reference estrogen (0.5μg ethinylestradiol (EE2)/kgbw/day), or vehicle. Exposure occurred by gavage to the dam from gestational day 6 until parturition, and then to the offspring from birth through weaning. Unbiased stereology was used to quantify the volume of the sexually dimorphic nucleus (SDN), the anteroventral periventricular nucleus (AVPV), the posterodorsal portion of the medial amygdala (MePD), and the locus coeruleus (LC) at postnatal day 28. No appreciable effects of BPA were observed on the volume of the SDN or LC. However, AVPV volume was enlarged in both sexes, even at levels below the FDA NOAEL. Collectively, these data suggest the developing brain is vulnerable to endocrine disruption by BPA at exposure levels below previous estimates by regulatory agencies.

Figures

Figure 1. (A) Representative thionin stained coronal sections showing the sexually dimorphic nucleus (SDN).

Sections are arranged from rostral to caudal and the dotted line indicates the boundaries of the area measured. Perinatal exposure to BPA or EE2 had no significant effects on SDN volume in either sex (B). As expected, SDN volume was significantly larger in males than females in all exposure groups.
Significant sex differences in volume are represented by †††p ≤ 0.001. Error bars represent the 95% confidence interval and sample size is provided at the bottom.

Figure 2. (A) Representative thionin-stained coronal sections showing the anteroventral periventricular nucleus (AVPV).

Sections are arranged from rostral to caudal and the dotted line indicates the boundaries of the area measured. In females, perinatal exposure to 2.5, 25, and 2500 μg BPA/kg bw/day increased AVPV volume (B). In males, perinatal exposure to 25 and 2500 μg BPA/kg bw/day increased AVPV volume. As expected, AVPV volume was found to be significantly larger in females than males in all exposure groups. Exposure to 0.5 μg EE2/kg bw/day had no significant effects on AVPV volume.
Significant differences in volume compared to the same-sex vehicle group are represented by ***p ≤ 0.001, **p ≤ 0.01, and *p ≤ 0.05.
Significant sex differences in volume are represented by ††p ≤ 0.01, and †p ≤ 0.05. Error bars represent the 95% confidence interval and sample size is provided at the bottom.

Figure 3. In the right medial posterodorsal amygdala (MePD), perinatal exposure to 2500 μg BPA/kg bw/d increased MePD volume compared to the same sex vehicle controls.

However, overall evidence for BPA- and EE2- related effects were minimal and inconsistent on both the volume of the left and right MePD. In both the left and right MePD, volume was found to be significantly larger in males than females in all exposure groups.
Significant differences in volume compared the same-sex vehicle group are represented by **p ≤ 0.01.
Significant sex differences in volume are represented by †††p ≤ 0.001, ††p ≤ 0.01, and †p ≤ 0.05.
Error bars represent the 95% confidence interval and sample size is provided at the bottom.

Figure 4. (A) Representative thionin-stained coronal sections showing the posterodorsal subnucleus of the medial amygdala (MePD).

Sections are arranged from rostral to caudal. The dotted line indicates the boundaries of the area measured. Perinatal exposure to BPA or EE2 had no significant effects on MePD volume (B). MePD volume was larger in males than females in all exposure groups.
Significant sex differences in volume are represented by †††p ≤ 0.001, and ††p ≤ 0.01. Error bars represent the 95% confidence interval and sample size is provided at the bottom.

Figure 5. (A) Representative thionin-stained coronal sections showing the locus coeruleus (LC).

Sections are arranged from rostral to caudal. The dotted line indicates the boundaries of the area measured. LC volume was significantly increased in males perinatally exposed to 0.5 μg EE2/kg bw/day (B). BPA had no effects on LC volume.
Significant differences in volume compared the same-sex vehicle group are represented by *p ≤ 0.05. Error bars represent the 95% confidence interval and sample size is provided at the bottom.

Tables

Table 1. Effect of Sex and Perinatal BPA or EE2 Exposure on the Volume of Juvenile Rat Brain Nuclei.