Elsevier

Hormones and Behavior

Volume 62, Issue 4, September 2012, Pages 480-490
Hormones and Behavior

Gestational and lactational exposure to bisphenol-A affects anxiety- and depression-like behaviors in mice

https://doi.org/10.1016/j.yhbeh.2012.08.005Get rights and content

Abstract

Bisphenol-A (BPA), an environmental endocrine disruptor, has attracted attention because of its adverse effects on the brain and behavioral development. Previous evidence indicates that perinatal exposure to low levels of BPA affects anxiety-like and cognitive behaviors in adult rodents. The present study aims to investigate the changes of anxiety- and depression-like behaviors of perinatally exposed mice in adulthood following the gestational (gestation days 7 to 20) or lactational (postnatal days 1 to 14) exposure to BPA (0.4 or 4 mg/kg/d). The results indicated that both gestational and lactational exposures to BPA increased anxiety- and depression-like behavior in mice of both sexes. The females with gestational exposure exhibited an increased anxiety-like state in the four models tested, including the open field, dark–light transition task, mirrored maze, and elevated plus maze tasks. Furthermore, the females with lactational exposure and the males with gestational exposure exhibited an anxiogenic-like behavior in two models, whereas the males with lactational exposure exhibited an anxiogenic-like behavior only in the elevated plus maze test. The results of the forced swim task showed that gestational exposure markedly increased the immobile time in both sexes, and the same effect was induced by lactational exposure only with 4 mg/kg/d BPA. Furthermore, western blot analyses showed that both gestational and lactational exposures inhibited the expression of the AMPA receptor subunit GluR1 in the hippocampus and amygdala in mice of both sexes, whereas the level of the NMDA receptor subunit NR1 was increased in the amygdala following gestational exposure but was reduced in the hippocampus of the females with lactational exposure. These results suggest that both gestational and lactational exposures to BPA increased anxiety- and depression-like behaviors of adult mice of both sexes. In addition gestational exposure exhibited a stronger effect on anxiety-like state in females. The altered levels of AMPA and NMDA receptors in the hippocampus and amygdala may be associated with BPA-induced behavioral changes.

Highlights

► Gestational or lactational exposure to BPA enhanced anxiety of mice. ► Gestational or lactational exposure to BPA enhanced depression of mice. ► Gestational exposure to BPA had a stronger effect on anxiety in females. ► The level of AMPA receptor in hippocampus and amygdale is reduced by BPA.

Introduction

Gonadal hormones play a critical role in the sexual differentiation of the brain that happens early during development, from late embryogenesis to the early postnatal period. Thus gonadal hormones determine behavior patterns throughout life. It was reported that estrogen-induced synaptic changes during the critical period of development affected the formation of neuronal circuits for sexually dimorphic behaviors (Ohtani-Kaneko et al., 2010). BPA, an environmental endocrine disruptor, has estrogenic and anti-estrogenic properties (Negishi et al., 2004, Xu et al., 2011a). Recent studies found that perinatal exposure BPA, at levels below the no-observed-adverse-effect level (NOAEL) (BPA < 50 mg/kg/d), did not affect the reproductive system, but influenced the processes of sexual differentiation of the brain and behaviors in offspring rodents (Fujimoto et al., 2006, Fujimoto et al., 2007, Gioiosa et al., 2007, Zhang et al., 2009). These findings suggest a high susceptibility of the central nervous system (CNS) to BPA during early development.

Anxiety behaviors are influenced by the developmental estrogen environment. Several studies have provided evidence for the complex effects of estrogen on anxiety. In normal cycling women, a low estrogen level during the premenstrual phase is considered to be the reason for anxiety symptoms (Pandaranandaka et al., 2006). The ovariectomized (ovx) rodents supplemented with estrogens were found to be anxiolytic (Koss et al., 2004), anxiogenic (Morgan and Pfaff, 2002), or unchanged (Imwalle et al., 2005). An increasing number of studies have reported the influence of developmental exposure to BPA on anxiety- and depression-like behaviors in rodents; however, the results were inconsistent (Table 1) (Cox et al., 2010, Farabollini et al., 1999, Fujimoto et al., 2006, Gioiosa et al., 2007, Nakamura et al., 2012, Negishi et al., 2004, Patisaul and Bateman, 2008, Ryan and Vandenbergh, 2006, Tian et al., 2010, Zhang et al., 2009). Independent of the dosage and age of the animal, the exposure period is a crucial determining factor for the BPA effects on behaviors. Organisms exposed to endocrine disruptors, such as BPA, during embryonic, fetal or neonatal life would present a predisposition to dysfunctions that manifest during puberty or adulthood. Therefore, an important experimental approach is to study the effect of an equal dosage of BPA administered for different exposure periods on behavioral tasks. Maternal BPA can be transferred either to the fetus across the placenta during pregnancy, or to the nursing infant through breast milk during lactation. Thus, maternal BPA interferes with the effects of endogenous estrogen on brain development (Doerge et al., 2010, Snyder et al., 2000, Takahashi and Oishi, 2000). It was found that following the maternal administration of BPA, the maximal concentration of BPA in fetuses reached 61% of that present in maternal blood (Takahashi and Oishi, 2000), and the level of aglycone BPA in breast milk was 1.58-fold of that present in maternal serum (Doerge et al., 2010). In the present study, we chose either prenatal or postnatal BPA exposure to compare the effects of gestational and lactational BPA exposure on anxiety- and depression-like behaviors, as observed through several behavioral tasks.

Anxiety may be both accompanied by the symptoms of depression and a precursor for the development of depression (Breslau et al., 1995). The brain targets for the estrogen effects on anxiety and depression include the hippocampus and amygdala which have long been considered to be important components of the limbic system and regulators of the hypothalamic–pituitary–adrenal (HPA) response (Walf and Frye, 2006). Thus, we believe that the hippocampus and/or amygdala may be targets for the BPA effects on anxiety and depression. In addition, anxiety- and depression-related behaviors are regulated by various neurotransmitter systems in the brain. Behavioral studies have drawn attention to the participation of both glutamatergic N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the mediation of fear and anxiety (Carobrez et al., 2001, Chourbaji et al., 2008). It was reported that NMDA and AMPA receptors participate in synaptic transmission during the acquisition and/or expression of fear in the basolateral nuclei of the hippocampus and amygdala (Chourbaji et al., 2008). NMDA receptor antagonists, acting on different sites of the receptor complex, can reduce anxiety in both humans and experimental animals (Barkus et al., 2010). Studies with transgenic animals showed that anxiety was inhibited by the hippocampal-specific NMDA receptor subunit NR1 deletion (Barkus et al., 2010), but was enhanced by the AMPA receptor subunit GluR1 deletion (Xiang et al., 2011). Thus, BPA may affect anxiety and depression behaviors through the modulation of the glutamatergic system. To elucidate the relationship between the BPA-induced behavioral alterations and the glutamatergic system in the CNS, we further examined the expressions of NMDA receptor subunit NR1 and AMPA receptor subunit GluR1.

Section snippets

Animals

Male (30–35 g) and female (25–30 g) ICR mice were purchased from the Experimental Animal Center, Zhejiang Academy of Medical Science, and maintained on a 12:12 h light:dark cycle (with the lights turned off from 20:00 to 8:00 h) with free access to food and water. All animals were fed a soy-free diet upon arrival and for the duration of the experiment. All experiments in the present study were conducted in accordance to the Care and Use Standard of the Laboratory Animal (China Ministry of Health

Body weight and the ratio of reproductive organ weight to body weight

There was a significant difference in the body weight of mice between the sexes (female body weight < male body weight), at the age of 8 weeks, regardless of BPA exposure. A significant interaction for exposure period × BPA treatment was found for the body weight at an age of 8 weeks of the male or female offspring (female F(2,54) = 10.219, p < 0.001; male F(2,54) = 9.292, p < 0.001). Gestational or lactational exposure to BPA had significant effects on body weight within each gender (gestational exposure

Discussion

The developmental period from late embryogenesis to early postnatal is critical for the estradiol (E2)-induced formation of neuronal circuits related to sexually dimorphic behaviors. The level of hormone during this critical developmental period becomes a determining factor impacting the sex differentiation of the brain and behaviors (Ohtani-Kaneko et al., 2010). A growing body of evidence indicated that perinatal maternal exposure to low levels (< 50 mg/kg/d) of BPA, an environmental endocrine

Acknowledgments

The present study was supported by the National Natural Science Foundation of China (Nos. 30872087 and 81172627) and the Zhejiang Province Natural Science Foundation (No. Z2090955).

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