Hyperactivity of basolateral amygdala mediates behavioral deficits in mice following exposure to bisphenol A and its analogue alternative
Graphical abstract
Introduction
Bisphenol A (BPA) is a type of endocrine disrupting chemical. At present, there is more than 5 million tons demanding of BPA each year for industrial production, with over 100 tons released into the atmosphere (Vandenberg et al., 2009). In daily life, approximately 90% of people are unintentionally exposed to BPA through diet (>90%) and skin absorption (<5%) (Geens et al., 2012). Adverse effects of BPA on human health are well documented (Rochester, 2013). Of note, BPA exposure in early life can cause behavioral problems in children, such as depression, anxiety, and social deficits (Evans et al., 2014; Harley et al., 2013; Perera et al., 2016). Several developed countries have restricted the use of BPA in materials, including plastics, food contact products, and coatings (Chen et al., 2016). As such, there is growing demand for BPA substitutes with similar physical and chemical properties. Bisphenol S, F, and AF (BPS, BPF, and BPAF, respectively), which contain two hydroxyphenyl functional groups, are commonly used as BPA alternatives (Chen et al., 2016). Among these bisphenols, BPS with rigid OSO double bonds shows greater thermal and light stability than BPA (Asimakopoulos et al., 2016) and is widely used for producing “BPA-free” consumer products, such as baby bottles, thermal receipt papers, and food can linings (Liao et al., 2012b). Notably, BPS had been frequently detected in river water and indoor dust samples in China, Japan, and Korea (Yamazaki et al., 2015). Furthermore, detectable concentration of BPS in urine (0.013–1.67 μg/g) has been found in 81% of surveyed people (n = 351) 81% from Japan, China, United States, Kuwait, Vietnam, Malaysia, India, and Korea (Liao et al., 2012a). Even, concentration of BPS in urine sample is higher than BPA in Jeddah (Asimakopoulos et al., 2016). Several zebrafish studies have shown that BPS can induce oxidative stress in the brain (Salahinejad et al., 2021) and cognitive and social deficits (Naderi et al., 2020; Salahinejad et al., 2020). However, whether BPS is a safe BPA alternative regarding impact on mammalian behavior is insufficiently understood.
During human development, the weight of gray matter in the brain reaches a peak at the end of the juvenile stage (~12 years old), a time during which various behaviors are refined by experience (Sugiyama et al., 2009). In addition, during the juvenile stage, the gonads release relatively stable amounts of estrogen, which provides a good time window for exploring the impact of environmental estrogen on human health (Giedd et al., 1999). Here, we chose juvenile mice to evaluate the effects of BPA and its alternative BPS on mammalian behavior. The reference daily limit of BPA for human exposure given by the US Environmental Protection Agency (EPA) is 50 μg/kg/day. In 2015, the European Food Safety Authority (EFSA) lowered the tolerable daily intake (TDI) value from 50 μg/kg/day to a temporary (t)-TDI of 4 μg/kg/day. As pharmacokinetic studies on BPA accumulation and elimination in the human body is still uncertain, it may be more reasonable to calculate BPA doses for animals based on their surface area factor (9.01) to humans. Hence, 4 and 50 μg/kg/day for humans is the equivalent of ~36.04 and 450.5 μg/kg/day (0.036 and 0.45 mg/kg/day), respectively, for mice. In addition, based on an environmentally relevant concentration of BPS of 100 μg/kg (body weight) (Guo et al., 2021), the equivalent BPS exposure in mice should be ~0.9 mg/kg/d. Thus, based on these standards, we chose 0.1 (low) and 1 (high) mg/kg/day as the exposure levels for BPA and BPS in the present study. The basolateral amygdala (BLA) is implicated in the modulation of socially and emotionally driven behaviors (Huang et al., 2020; Tovote et al., 2015). By electrophysiological recording, we analyzed neuronal firing rates and local field potential (LFP) in the BLA for assessing the local physiological activation in mice with or without exposure to BPA and BPS. In addition, glutamate receptor expression was detected in the BLA of each mouse. This study not only provide valuable evidence of BPA and BPS-induced behavioral impairments, but also a quantitative basis for industrial production of BPS as a BPA alterative.
Section snippets
Chemicals
BPA (CAS: 80-05-7), BPS (CAS: 80-09-1), and dimethyl sulfoxide (DMSO; CAS: 67-68-5) were purchased from Sigma-Aldrich (USA). Stock solutions of BPA and BPS (50 mg/ml) were prepared by dissolving 500 mg of BPA and BPS in 10 ml of DMSO, respectively. Other chemical reagents were of analytical grade and purchased from the China National Pharmaceutical Group Corp (Beijing China).
Animals and treatments
Juvenile C57 BL/6J mice (80 males) were purchased from the Beijing Experimental Animal Center (China) and used for
Effects of juvenile exposure to BPA and its alternative BPS on depressive-like behavior
To assess the behavioral effects of BPA and BPS on mice, we first detected their levels in serum after juvenile exposure. As shown in Fig. 1A, BPA concentrations in serum samples from 0.1 to 1 mg/kg/d BPA exposed mice increased significantly to 1.69 ± 0.40 ng/ml and 14.23 ± 3.25 ng/ml, respectively, compared to that of the control group (p < 0.001, F (2, 19) = 17.14, one-way ANOVA followed by Bonferroni's post hoc test). Additionally, serum BPS level increased to 2.50 ± 1.48 ng/ml and
Discussion
Here, we examined the effects of BPA and BPS on mouse behavior after juvenile exposure (P21–P49). We found that both BPA (0.1 and 1 mg/kg/d) and BPS (1 mg/kg/d) induced depression, anxiety, and social deficits in mice. These behavioral changes were accompanied by neural hyperactivation in the BLA, i.e., increased excitatory receptor expression and enhanced neuronal firing and LFP power. However, low-dose BPS (0.1 mg/kg/day) had no negative effects on depression and anxiety-like behavior, or BLA
Credit author statement
Conceived and designed the experiments: Fan HU. Performed the experiments: Weifeng Liang, Linke Zhang, Huan Wang and Muzi Li. Analyzed the data: Weifeng Liang, Linke Zhang, Huan Wang and Muzi Li. Wrote the paper: Weifeng Liang, Fan HU.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was supported by the National Natural Science Foundation of China, China (21876041 and 21307024).
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