Gestational and lactational exposure to bisphenol-A affects anxiety- and depression-like behaviors in mice
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).
References (54)
- et al.
Hippocampal NMDA receptors and anxiety: at the interface between cognition and emotion
Eur. J. Pharmacol.
(2010) - et al.
Anxiety disorders: sex differences in prevalence, degree, and background, but gender-neutral treatment
Gend. Med.
(2007) - et al.
Glutamate and anxiety
Eur. Neuropsychopharmacol.
(2004) - et al.
Sex differences in depression: a role for preexisting anxiety
Psychiatry Res.
(1995) - et al.
Modulation of defensive behavior by periaqueductal gray NMDA/glycine-B receptor
Neurosci. Biobehav. Rev.
(2001) - et al.
Gestational exposure to bisphenol A and cross-fostering affect behaviors in juvenile mice
Horm. Behav.
(2010) Exploratory behavior models of anxiety in mice
Neurosci. Biobehav. Rev.
(1985)- et al.
Lactational transfer of bisphenol-A in Sprague–Dawley rats
Toxicol. Lett.
(2010) - et al.
Perinatal exposure to the estrogenic pollutant bisphenol A affects behavior in male and female rats
Pharmacol. Biochem. Behav.
(1999) - et al.
Estrous cycle and sex differences in performance on anxiety tasks coincide with increases in hippocampal progesterone and 3alpha, 5alpha-THP
Pharmacol. Biochem. Behav.
(2000)
Environmental impacts on brain functions: low dose effects of bisphenol A during perinatal critical period
International Congress Series
Prenatal exposure to bisphenol A impairs sexual differentiation of exploratory behavior and increases depression-like behavior in rats
Brain Res.
Developmental exposure to low-dose estrogenic endocrine disruptors alters sex differences in exploration and emotional responses in mice
Horm. Behav.
Effects of prenatal and postnatal exposure to a low dose of bisphenol A on behavior and memory in rats
Environ. Toxicol. Pharmacol.
Lack of functional estrogen receptor beta influences anxiety behavior and serotonin content in female mice
Physiol. Behav.
Sex differences in animal tests of anxiety
Physiol. Behav.
Different effects of subchronic doses of 17β-estradiol in two ethologically based models of anxiety utilizing female rats
Horm. Behav.
The mirror chamber test for testing anxiolytics: is there a mirror-induced stimulation?
Physiol. Behav.
Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors
Biol. Psychiatry
Estrogen's effects on activity, anxiety, and fear in two mouse strains
Behav. Brain Res.
Prenatal and lactational exposure to low-doses of bisphenol A alters adult mice behavior
Brain Dev.
Effects of estrogen on synapsin I distribution in developing hypothalamic neurons
Neurosci. Res.
Animal models of anxiety and depression: how are females different?
Neurosci. Biobehav. Rev.
Anxiolytic property of estrogen related to the changes of the monoamine levels in various brain regions of ovariectomized rats
Physiol. Behav.
Differential effects of exogenous and endogenous estrogen on anxiety as measured by elevated T-maze in relation to the serotonergic system
Behav. Brain Res.
Neonatal exposure to endocrine disrupting compounds or an ERβ agonist increases adult anxiety and aggression in male rats
Horm. Behav.
Corticosterone-regulated actions in the rat brain are affected by perinatal exposure to low dose of bisphenol A
Neuroscience
Cited by (80)
Environmental toxicology of bisphenol A: Mechanistic insights and clinical implications on the neuroendocrine system
2024, Behavioural Brain ResearchAdulthood bisphenol A exposure induces anxiety in male mice via downregulation of alpha-1D adrenergic receptor in paraventricular thalamus
2023, Ecotoxicology and Environmental SafetyDysfunction of the medial prefrontal cortex contributes to BPA-induced depression- and anxiety-like behavior in mice
2023, Ecotoxicology and Environmental Safety