The environmental estrogen bisphenol a inhibits estradiol-induced hippocampal synaptogenesis

Abstract

Bisphenol A (BPA) is an estrogenic chemical that is widely used in the manufacture of plastics and epoxy resins. Because BPA leaches out of plastic food and drink containers, as well as the BPA-containing plastics used in dental prostheses and sealants, considerable potential exists for human exposure to this compound. In this article we show that treatment of ovariectomized rats with BPA dose-dependently inhibits the estrogen-induced formation of dendritic spine synapses on pyramidal neurons in the CA1 area of the hippocampus. Significant inhibitory effects of BPA were observed at a dose of only 40 microg/kg, below the current U.S. Environmental Protection Agency reference daily limit for human exposure. Because synaptic remodeling has been postulated to contribute to the rapid effects of estrogen on hippocampus-dependent memory, these data suggest that environmental BPA exposure may interfere with the development and expression of normal sex differences in cognitive function, via inhibition of estrogen-dependent hippocampal synapse formation. It may also exacerbate the impairment of hippocampal function observed during normal aging, as endogenous estrogen production declines.

Figure 1. BPA inhibits the effect of 17β -E₂ on CA1 PSSD. (A) At 30 min after 17β -E₂ injection, PSSD increased by almost 100%. (B) The PSSD response to 17β -E₂ is inhibited in a dose-dependent manner by coadministration of BPA. Data in all cases represent mean ± SD of independent observations from three rats at each dose level. In the case of the 120-μg/kg dose, the bars indicating SD are so close to the mean that they are partially obscured by the symbol. The line through the points represents the four-parameter logistic best-fit regression analysis of the data. The ED₅₀ for BPA inhibition of the 17β -estradiol–induced increase in PSSD, calculated from the four-parameter curve fit, is 117 μg/kg. : *Significantly different from oil-injected controls (p < 0.001, Student t-test). : **Significantly different from PSSD in animals treated with 17β -E₂ alone (Bonferroni-Dunn post hoc test, p < 0.05).

Figure 2. High-power electron micrographs taken from the CA1 stratum radiatum of rats treated with either (A) 60 μg/kg 17β -E₂ or (B) 60 μg/kg 17β -E₂ + 400 μg/kg BPA. Arrows indicate spine synapses. Bar = 500 nm.

Figure 3. BPA administration only slightly impairs the uterotrophic response to 17β -E₂. Two-way ANOVA: 17β -E₂ effect, F = 301.2, df 1,8, p < 0.0001; BPA effect, F = 11.1, df 1,8, p = 0.01; 17β -E₂ × BPA interaction, F = 0.29, df 1,8, p > 0.6.

Figure 4. BPA inhibits the effects of 17α -E₂ on CA1 PSSD. In the absence of BPA, 17α -E₂ induced an increase in synapse density of 0.463 synapses/μm³, a 65% increase above the mean synapse density in vehicle-injected controls. In the presence of BPA, the effect of the estrogen was reduced to an increase of 0.192 synapses/μm³, 39% above the level observed in animals treated with BPA alone. Two-way ANOVA: 17α -E₂ effect, F = 237.3, df 1,8, p < 0.0001; BPA effect, F = 292.8, df 1,8, p < 0.0001; 17α -E₂ × BPA interaction, F = 40.8, df 1,8, p = 0.0002. : *Significantly higher PSSD than in vehicle-treated rats, without BPA (Student t-test, p < 0.05). : **Significant inhibitory effect of BPA compared with animals given the same vehicle or 17α -E₂ without BPA (Bonferroni-Dunn post hoc test, p < 0.05).