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, 5 (3), 828-835
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Perinatal Exposure to Low-Dose Bisphenol A Disrupts Learning/Memory and DNA Methylation of Estrogen Receptor Alpha in the Hippocampus

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Perinatal Exposure to Low-Dose Bisphenol A Disrupts Learning/Memory and DNA Methylation of Estrogen Receptor Alpha in the Hippocampus

Huailong Chang et al. Toxicol Res (Camb).

Abstract

Developmental exposure to bisphenol A (BPA) has been indicated to pose long-lasting effects on brain development and behaviors in adulthood. Previous studies have also shown that BPA may disrupt the epigenetic programming of genes in the brain. Here, we focused on investigating the effects of perinatal exposure to low-dose BPA on learning/memory function and emotional regulation, as well as the associated molecular events. Pregnant Sprague-Dawley (SD) rats were treated with control corn oil or BPA (40 μg kg-1 per day) throughout gestation and lactation. Morris water maze (MWM) and elevated plus maze (EPM) were used to evaluate learning/memory and anxiety-like behaviors at postnatal day (PND) 60 and 85 respectively. The expression level of mRNA for estrogen receptors (ER), ERα and ERβ, in the hippocampus and the serum corticosterone level were determined, as well as the DNA methylation status of the ERα gene promoter. Perinatal exposure to BPA prolonged the escape latency independent of gender, and decreased the percentage of time spent in the target quadrant when examined in the MWM task. While no substantial alteration was observed in the EPM test, the serum corticosterone level was altered in a gender-specific manner. BPA also decreased the expression of mRNA for ERα in the hippocampus, along with elevated DNA methylation of the ERα gene promoter. These results suggest that perinatal exposure to BPA impairs learning/memory function and elevated DNA methylation of the ERα gene in the hippocampus may be involved.

Figures

Fig. 1
Fig. 1. Effects of BPA on the escape latency (A); swimming distance (B); and swimming velocity (C) in the training days of the MWM test. (D) Shows the time spent in the target quadrant in the probe test. Data were presented as mean ± SEM; both control (n = 24) and BPA (n = 26) groups have equal numbers of female and male rats; ††, the BPA group differed significantly from the control group regardless of the gender (p < 0.01); §§, the BPA females differed significantly from the control females (p < 0.01). *p < 0.05 versus control of the same gender.
Fig. 2
Fig. 2. Anxiety-like behaviors assessed by the elevated plus maze (EPM). Anxiety-like behaviors were assessed with (A) total entries into the open arms, (B) percentage of entries into the open arms, (C) time spent in open arms, and (D) percentage of time spent in the open arms. Percentages were calculated by dividing the open arm entries and time with the sum of entries and the total time. Data were presented as mean ± SEM; n = 18 (10 females, 8 males) and 23 (12 females, 11 males) for control and BPA groups respectively; **p < 0.0 l versus control of the same gender. (E) shows the serum corticosterone level. Data were presented as mean ± SEM; n = 12 with equal numbers of male and female rats; **p < 0.0 l versus control of the same gender; #p < 0.05, ##p < 0.01 versus females with the same treatment.
Fig. 3
Fig. 3. Expression of mRNA for ERα (A) and ERβ (B) in the hippocampus. Data were presented as mean ± SEM; n = 12 with equal numbers of male and female rats; *p < 0.05, ***p < 0.001 versus control of the same gender; # p < 0.05 versus females with the same treatment.
Fig. 4
Fig. 4. Effects of BPA exposure on the methylation status of the promoter region of the ERα gene in the hippocampus. (A) Schematic illustration of the promoter regions of the human (hER) and rat (rER) genes. Percentages represent the degree of homology between these two species. Red font: position of the PCR primers; Underlined: analyzed CpG sites; +1 and Green font: transcription start site. DNA methylation of 17 CpG sites in the ERα promoter was examined in female (B) and male (C) hippocampi. Methylation of CpG site 14 was not detected. Data were presented as mean ± SEM; n = 6 with equal numbers of male and female rats; *p < 0.05, ***p < 0.001 versus control of the same gender.

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