Introduction
Bisphenol A (BPA) is used widely as a raw material in plastic and epoxy resin, so people have many opportunities to contact in their daily life. BPA can be detected in blood, urine, and placenta in the range of 0.5 to 2 ng/mL.[1,2] Because of the adverse effects on human health and the environment, the application of BPA substitutes has gradually increased, and bisphenol analogs such as bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF) have been detected in the human body.[3] Oxidative DNA and RNA damage is directly related to the presence of BPA and bisphenol analogs in humans.[4] BPA and bisphenol analogs can interfere with endocrine function by binding with classic estrogen receptors ERα and ERβ, estrogen-related receptors (ERR), or G protein estrogen receptor, as an endocrine disruptor, disturbing the development and maturation of male germ cells, and increasing the risk of hormone-dependent tumors, such as breast cancer and endometrial cancer.[5,6] Beyond the reproductive system, bisphenols also affect the human liver, lungs, and other organs. BPA and BPF also be detected in the brain,[7] and suggesting that BPA and bisphenol analogs may act on nerve tissues by passing through the blood-brain barrier, allowing them to affect the development and function of the nervous system and increase the risk of neuropsychiatric diseases.[8]
Effects of BPA on Learning and Memory Ability
The normal number, function, and structure of hippocampal neurons are important to maintain learning and memory ability [Table 1]. Dendritic arborization is required for appropriate connection and information transmission between neuronal cells, while dendritic spines provide the morphological and structural basis for neural plasticity. Early studies found that neurons in the hippocampus and prefrontal cortex were some of the main targets of BPA.[9] Recent researches have focused on the effects of BPA in the hippocampus and prefrontal cortex, which are closely related to cognitive function, on account of the start time, dosage, and duration of BPA exposure.[10-12] In rodents and non-human primates, maternal exposure to BPA in the embryonic period typically resulted in a spectrum of learning and spatial memory impairments, and the changes in the number of pyramidal cells and the complexity of dendrites in the hippocampal cornu ammonis (CA1). The impacts on the learning and memory ability, as well as the structural abnormalities of nerve tissue, were different between those exposed to BPA in adolescence and adulthood.
Table 1 -
Neural effects of BPA in different genders.
| Effects of BPA |
|
Prenatal or perinatal exposure |
Postnatal exposure |
| Study and memory disorders |
Spatial memory |
No sex differences
[13]
|
Male only
[14]
|
|
Passive avoidance memory |
Male only
[13]
|
|
|
Learning and memory ability |
Male only
[15]
|
|
|
Non-spatial memory, object recognition |
|
Male only
[16]
|
| Morphological and functional changes in neuron |
Number ↓ |
Male only in low concentration
[13]
|
|
|
Decreased dendritic length and density |
Male only
[15]
|
Male: Low, medium, and high concentration BPA;
Female: Low and high concentration BPA
[14]
;
No sex differences
[17,18]
|
|
Neurotransmitters and neurotrophic factors |
Male: GABA↓, 5-HT↓
Female: GABA/Glu/5-HT/DA ↑
[13]
Male: BDNF ↓;
Female: BDNF ↑
[19]
|
|
GABA: γ-aminobutyric acid; 5-HT: 5-hydroxytryptamine; BPA: Bisphenol A; BDNF: Brain-derived neurotrophic factor; Glu: Glutamic acid; DA: dopamine.
For non-human primates, embryo or adult exposure to BPA in Rhesus monkeys, asymmetric excitatory synapses of pyramidal cells decreased in the CA1 area, while the synapses in the II/III layer of the dorsolateral prefrontal cortex, the region related to working memory, remained unchanged.[17,20] When adult male Vervet monkeys were exposed to BPA, the synapses of pyramidal cells in the hippocampal CA1 decreased significantly, accompanied by a decreased working memory accuracy, subsequent removal of BPA was able to improve memory function and increase the number of dendritic spines, but adolescents exposed to BPA for 30 days, synapses in the same hippocampal CA1 area or in the dorsolateral pyramidal cells of prefrontal lobe were unchanged, and no obvious cognitive impairments were observed, even serum concentrations reached 10 ng/mL.[17] Thus, these results demonstrated that pyramidal cells in the hippocampal CA1 and the prefrontal cortex II/III layer, which were sensitive to BPA and closely related to learning and memory ability, respond differently to BPA exposure at different stages of non-human primate development. Prenatal BPA exposure affected the neural development, and neurons in the CA1 were more susceptible to BPA than those in the prefrontal lobe in this context, but in adulthood, neurons in these two regions exhibited similar sensitivity to the neurotoxicity of BPA. Although exposure patterns of BPA were different between the two periods, indirect maternal exposure vs. direct exposure by cortical injection in adulthood, blood concentrations of BPA in the experimental animals were lower than 1 ng/mL, similar to concentrations actually detected in human peripheral blood.[17] In contrast to embryonic and adult exposure, BPA had no significant effects on neurons in the hippocampus or dorsolateral prefrontal cortex of adolescent experimental animals, even though blood concentrations of BPA reached 10 ng/mL, 10 times higher than gestational and adulthood exposure, and the duration of exposure was the same as in adulthood (30 days). The effects of BPA exposure during adolescence and adulthood on cognitive function and brain structure were examined immediately after the exposure, and it is not clear why hippocampal and dorsolateral prefrontal cortex neurons are more tolerant to BPA in adolescence than those in adulthood. It has been speculated that adverse factors, such as local oxidative stress and inflammation, may be more obvious in the brain of adult animals, thus increasing susceptibility to BPA. In addition, it is unclear whether exposure to low concentrations of BPA for 30 days can produce long-term effects.
The abnormalities of the rodent brains induced by prenatal or perinatal BPA exposure were similar to those seen in non-human primates, and the learning and memory disorders may persist until adulthood. Mice were exposed to BPA at 400 μg · kg−1 · day−1 or 40 μg · kg−1 · day−1 for 10 days. The dose was several times higher than the safe reference dose or close to the safe reference dose, respectively (reference safe daily limit of 50 μg · kg−1 · day−1 set by the United States Environmental Protection Agency (USEPA) [tolerable daily intake (TDI) U.S. EPA., 2015]).[21] The basal dendrites complexity of pyramidal cells in the hippocampal CA1 was decreased at postnatal day 21, and the density of dendritic spines in the same region was significantly lower at 14 months after birth for BPA-treated mice than for those in the control group. Basal dendrite length and dendritic branches far from the cell body were both decreased in the high-concentration exposure group at postnatal day 21, but no such changes were observed in the low-concentration exposure group. It has been suggested that embryonic BPA exposure may affect the synaptic formation and information transmission of hippocampal CA1 pyramidal cells, and these changes could persist for at least 14 months after birth.[22] In rats exposed to BPA from gestational day 6 to postnatal day 21, the impaired spatial memory, and decreased number and abnormal morphological changes of pyramidal cells in the hippocampal CA1 could be detected until adulthood, even though the adult offspring did not continue to ingest BPA after weaning. ERα expressed in the hippocampus, and N-methyl-D-aspartate receptor (NMDA) receptor subunit 2B (NR2B), phospho (p-NR2B), α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor 1 (GluA1), phospho-GluA1 (p-GluA1), postsynaptic density 95 (PSD-95), synapsin I, protein kinase C (PKC), phosphorylated extracellular signal-regulated kinase (p-ERK), and phospho-cyclic adenosine monophosphate (cAMP) response element binding protein (p-CREB), which are closely related to synaptic plasticity, were decreased.[13] Indirect exposure to BPA during the embryonic and early postnatal stages, even at levels below the safe reference concentration, may not only affect brain development but can also have long-term effects on the synaptic plasticity of hippocampal neurons in adulthood or during aging. In addition, for pregnant animals exposed to BPA, abnormalities can be detected not only in the first generation but also in the second generation. In mice exposed to BPA from pregnancy to 21 days after birth, offspring showed abnormal learning and memory ability, and the neuron numbers in the hippocampal CA1/CA3 and the dentate gyrus, the length of dendrites and the density of dendritic spines were all decreased. Although the first generation did not ingest BPA after weaning, decreased neurons in the hippocampus and dentate gyrus and abnormal dendritic spines density in the CA1 area were still detected in the second generation, however, DNA damage only occurred in the first generation and did not spread to the second generation.[15]
The neural development of rodents continues until puberty, so exposure to BPA during this period still can affect the development and maturation of hippocampal neurons, and exposed animals are characterized by abnormal learning and memory ability [Table 1]. After exposure to BPA from postnatal day 7 to 21, dendritic spines in the hippocampal CA1 and dentate gyrus decreased, the levels of glutamic acid (Glu) and acetylcholine (Ach) increased, while the 5-hydroxytryptamine (5-HT) and γ-aminobutyric acid (GABA) decreased, which leads to an unbalanced Glu/GABA ratio, associated with the impaired spatial learning and memory ability.[14] Continuous exposure to BPA for 8 weeks from postnatal day 21 resulted in a decreased complexity of dendrites on the neurons in hippocampal CA1 and dentate gyrus, and the density of dendritic spines and morphological changes were also significant, accompanied by the decreased activity-regulated cytoskeleton-associated protein (Arc) protein and increased postsynaptic membrane γ-aminobutyric acid type A receptor (GABAAR).[18] The Arc protein played an important role in the regulation of dendritic spines size and shape.[23] In addition, the start time of BPA exposure resulted in different effects on neurons, for example, dendritic development and maturation of hippocampal and dentate gyrus were affected by exposure to BPA within 3 weeks post-birth, while no remarkable effects were detected when exposure to BPA at 4 weeks post-birth, even at BPA concentrations 10 times higher than the safe reference dose.[24] Furthermore, neurons in hippocampus CA1 and CA3 showed different responses to BPA. BPA the same as or 10 times higher than the reference safe concentration resulted in decreased neuron numbers in the CA1, however, the neurons in the CA3 only decreased only when BPA was about 10 times higher than the USEPA reference safe daily limit.[24] There is no evidence to prove whether dentate gyrus neurons are more tolerant to BPA than hippocampal neurons. Six-week-old pubertal rats were exposed to BPA (40 μg · kg−1 · bw−1 [body weight]) for 1 week, and pyramidal cells in the hippocampal CA1 were marked by a reduced density of dendritic spines in rats at 7 weeks which persisted at 11 weeks and 13 weeks; at the same time, decreased dendritic spines density of II/III pyramidal cells in the medial prefrontal cortex was found at 7 weeks and 11 weeks, but was not significant at 13 weeks. The results for female rats were similar to those for male rats, but the density of basal dendritic spines of pyramidal cells in the medial frontal cortex decreased more significantly in males than that in females at 7 weeks and 11 weeks. It suggested that short-term BPA exposure during puberty, even at the levels below the USEPA reference safe daily limit of 50 μg · kg−1 · day−1, altered the dendrites of hippocampal CA1 pyramidal cells, and the alteration could continue into adulthood. During puberty, the effects of BPA on neurons in the CA1 were sex-independent, while in the medial prefrontal cortex BPA showed a gender-dependent result.[25] Similar to non-human primates, adult rats exposed to low concentrations of BPA showed neurotoxicity in the hippocampus and medial prefrontal lobe, as well as a loss of spatial memory ability [Figure 1].[12]
;)
Figure 1: Neural abnormalities involved with learning and memory disorders induced by BPA. Maternal exposure to BPA induced decreased pyramidal cells, dendrite complexity, and asymmetric excitatory synapses in hippocampus CA1 of Rhesus monkey; pre- and postnatal exposure to BPA caused decreased dendrite length and complexity, accompanied by abnormal synaptic plasticity-related signals and neurotransmitters unbalance in hippocampus CA1 and dentate gyrus of rodents. BPA: Bisphenol A; CA1: Cornu ammonis1.
BPA exposure tends to impair neurons in the hippocampus, particularly the CA1 region, and may lead to various learning and memory disorders. Differences in outcome have been associated with the time of initial exposure to BPA and the exposure duration. In addition, the impacts of BPA on male animals were more obvious, while female animals seem to have a certain resistance to BPA, especially with regard to learning and memory. Studies have shown that exposure to BPA in pregnant animals resulted in offspring with impaired learning ability, as well as abnormalities in the number or morphology of neurons in the hippocampus and prefrontal lobe. It is not clear whether BPA acts directly on the embryo, or if BPA affects fetal development by causing maternal dysfunction or inducing the secretion of harmful substances. BPA can pass through the placenta and can be detected in newborns,[25] so it can be speculated to act directly on the fetus to alter nervous system development. In both non-human primates and rodents, indirect prenatal or perinatal exposure to BPA at levels below the USEPA reference safe daily limit may affect the development and maturation of hippocampal neurons, however, the effects of postnatal or adolescent BPA exposure vary across species. No significant abnormalities were observed in the hippocampal or frontal lobe neurons of pubertal non-human primates exposed to BPA. In contrast, hippocampal neurons in rodents showed abnormal development and maturity, with hippocampal CA1 and CA3 neurons responding differently to different concentrations of BPA. Early exposure to BPA after birth also affected neurons in the dentate gyrus, although no effects were shown in the animals of BPA exposure at 4 weeks after birth. In addition, some damages caused by BPA in rodent embryos may extend to the second generation, these second-generation effects have not been detected in primates, and it is not clear whether they exist in these species.
Possible Effects of BPA on Neurodegenerative Diseases
The pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), remains largely unclear. Although genetic factors have been identified, many cases are sporadic, the morbidity increases with aging. It has been suggested that energy metabolism disorders, oxidative stress, local inflammation, excitatory neurotransmitters, and calcium overload are risk factors for these kinds of diseases [Table 2].[26-29] Although the impacts of bisphenols on neurodegenerative diseases have been studied at the cellular and overall levels, further extensive studies are still necessary.
Table 2 -
Effects of BPA on neurodegenerative diseases.
| Effects of BPA |
Prenatal exposure |
| AD |
|
 Progressive loss of memory;
Cognitive impairment;
Aβ plaques;
NFT |
Both sexes
[30,31]
: BACE1 ↑, NF-κB ↑, TNF-α ↑
Male
[32]
: APP ↑, p-tau ↑
Male
[33]
: p-JNK ↑, p-ERK ↑, PP2A ↓ |
| PD |
|
 Tremor;
Rigidity;
Bradykinesia;
Postural instability;
Decreased dopamine secretion |
Human
[34]
: Glucuronide-acidified BPA ↓;
Drosophila melanogaster
[35]
: AChE activity ↓, dopamine secretion ↓
Rhesus monkeys
[17]
: Dopaminergic neurons ↓ |
Aβ plaques: β-amyloid protein deposition; AChE: Acetylcholinesterase; AD: Alzheimer's disease; APP: Amyloid precursor protein; BACE1: Beta-site amyloid precursor protein cleaving enzyme 1; BPA: Bisphenol A; NF-κB: Nuclear factor kappa B; NFT: Neurofibrillary tangles; PD: Parkinson's disease; p-JNK: Phosphorylated c-Jun N-terminal kinase; PP2A: Protein phosphatase 2A; p-tau: Phosphorylated tau protein.
AD is characterized by a progressive loss of memory and cognitive impairment. β-Amyloid protein deposition (Aβ plaques) and neurofibrillary tangles (NFT) can be detected in the brain, and phosphorylated tau protein (p-tau) is the main component of NFT. In rats with prenatal exposure to BPA, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), NF-κB, and TNF-α mRNA were up-regulated, and increased BACE1 and NF-κB protein were also detected at the same time. BACE1 is a key enzyme involved in the proteolysis of amyloid precursor protein (APP) and is closely related to AD.[30,31] NF-κB and TNF-α play important roles in the inflammation, implying that prenatal BPA exposure may increase AD risk.[31] Increased APP and p-tau were detected in the hippocampus and frontal lobe of 7 week-old and 8 week-old male mice after subcutaneous injection of BPA for 30 days, which may be related to the abnormal insulin receptor (IR)–insulin receptor substrate (IRS)–protein kinase B (AKT)–glycogen synthase kinase 3 (GSK3) β signaling induced by BPA, GSK3β, and p-tau and lead to an increase in p-tau.[32] Although abnormal p-tau was not detected in 12 week-old adult male rats fed with BPA for 8 weeks, increased p-JNK and p-ERK as well as decreased phosphatase PP2A were detected in the brain, and changed kinases and phosphatase may increase the risk of p-tau accumulation.[33] Abnormal depositions of Aβ 42 and p-tau were also detected in vitro studies, SH-SY5Y or PC-12 cells treated by nanomolar BPA resulted in abnormal p-IR-p-IRS1 and AKT-GSK3 α/β signaling molecules, meanwhile, increased AD-related molecules, such as BACE-1, APP, β-carboxy terminal fragment (β-CTF), α-CTF, Aβ42, and p-tau, were detected. These findings suggest that BPA exposure increases the risk of AD potentially, and increased APP and p-tau were directly related to the abnormal insulin-IR-IRS1 signaling pathway induced by BPA [Figure 2].[36]
Figure 2: Possible AD risks involved with BPA. The rodents prenatally exposed to BPA showed increased BACE1, P-JNK/p-ERK and decreased PP2A, related to Aβ deposition and hyperphosphorylation of tau protein; increased NF-κB and TNF-α implicatedin a local inflammatory status; abnormal p-IR-p-IRS1 and AKT-GSK3 α/β signaling molecules in neuronal cells, which may relate to AD-related molecules, such as BACE-1, APP, β-CTF, α-CTF, Aβ42, and p-tau, leading to increased AD risk. α-CTF: α-carboxy terminal fragment; AD: Alzheimer's disease; AKT: Protein kinase B; APP: Amyloid precursor protein; BACE1: Beta-site amyloid precursor protein cleaving enzyme 1; β-CTF: β-carboxy terminal fragment; BPA: Bisphenol A; GSK3 α/β: Glycogen synthase kinase 3 alpha/beta; IR: Insulin receptor; IRS: Insulin receptor substrate; NF-κB: Nuclear factor kappa-B; p-ERK: Phospho-extracellular signal-regulated kinase; p-JNK: Phospho-c-Jun N-terminal kinase; PP2A: Protein phosphatase 2A; p-tau: Phosphorylated tau protein; TNF-α: Tumor necrosis factor-α.
PD is characterized by tremor, rigidity, bradykinesia, and postural instability and primarily involves decreased dopamine secretion from dopaminergic neurons in substantia nigra. The pathogenesis of non-hereditary PD is not completely elucidated. Studies have identified dopaminergic neurons as targets of BPA,[17] suggesting that BPA exposure may increase the risk of PD. Glucuronide-acidified BPA in the blood of PD patients was shown to be significantly lower than those of normal controls, but the mechanism underlying is unknown. BPA is excreted from the urine in this form.[34]Drosophila melanogaster exposed to 1 mmol/L BPA showed PD-like hypokinesia and decreased acetylcholinesterase (AChE) activity and dopamine secretion.[35] Dopaminergic neurons decreased in the ventral midbrains of Rhesus monkeys exposed to BPA at the same concentration in the human body in the last 2 months of pregnancy, suggesting that fetal exposure to low concentrations of BPA affected the development of dopaminergic neurons in the midbrain. However, no significant changes were detected on dopaminergic neurons in the striatum of Vervet monkeys exposed to the same concentration of BPA during adolescence (14–18 months after birth).[17]
These studies suggest that the prenatal exposure or direct exposure after birth to BPA can induce Aβ deposition and promote hyperphosphorylation of tau protein in the hippocampus, increasing the risk of AD. With respect to dopaminergic neurons, BPA primarily affects the development of embryonic dopaminergic neurons. Although adolescent exposure to BPA has no effect on dopamine in the striatum, it is not clear whether there are long-term effects on dopaminergic neurons, and further study is necessary to assess a possible BPA role in the pathogenesis of neurodegenerative diseases, due to its documented neurotoxicity.
Mechanisms Related with BPA Induced Nervous System Abnormality
Studies on non-human primates and rodents have shown that exposure to BPA at important stages of brain development, both before birth and during adolescence, impaired the development and maturation of the nervous system, characterized by decreased neurons in the hippocampus and prefrontal lobe, loss of dendrite complexity, ultimately resulting in abnormal cognitive function in experimental animals. The mechanisms underlying are not completely clear. Neural development is affected by estrogen, which is found not only in females but also in males.[37] BPA may cause adverse effects on brain development by interfering with the signals downstream of the estrogen receptor.[38] BPA exposure (0.1 mg/L BPA) from gestational day 11 to postnatal day 21 was associated with decreased blood thyroid hormone in both maternal and young rats. Although there were no significant differences in triiodothyronine (T3) or brain thyroxine (T4) between BPA-exposed rats and the control group at postnatal day 21, T3 levels in the prefrontal lobe and the hippocampus were lower in BPA-exposed rats at postnatal day 90, as were Ach, AChE and glucose metabolism.[39] Thyroid hormone promotes neural development, so BPA may affect nervous system development through thyroid hormone. In addition, exposure to BPA from gestational day 9 to day 21 was associated with the down-regulation of brain-derived neurotrophic factor (BDNF) mRNA and CYP19A1 mRNA in male offspring, and CYP19A1 also acted on estrogen production, as well as increased levels of DNA methyltransferase-1 protein, suggesting that prenatal BPA exposure may influence neural development through neurotrophic factors and epigenetic mechanisms.[19] Progenitor cells and neurogenesis in the dentate gyrus were also affected by BPA.[40] Beyond nerve cells, postnatal BPA exposure has been shown to reduce the number of oligodendrocytes in the hippocampus of young rats, with the effects lasting until adulthood.[41] In addition, BPA may also affect the development of peripheral nerve cells by affecting microglia.[42]
Direct exposure to BPA may cause neuronal cell energy metabolism disorders. Subcutaneous injection of low-dose BPA was shown to induce insulin resistance in male mice 7–8 weeks after birth, resulting in increased phosphorylation of IRS and a significantly decreased glucose transporter (GLUT) 1 and 3 in the hippocampus. GLUT1 is the main glucose transporter in vascular endothelial cells and astrocytes, while GLUT3 plays an important role as glucose transporter in neurons.[32] BPA was also shown to disrupt IRs and downstream signaling in vitro, leading to decreased p-IR and increased inhibitory p-IRS1 in SH-SY5Y neuronal cells.[36]
BPA induces oxidative stress and inflammation by directly affecting the mitochondrial oxidative respiratory chain and inhibiting peroxide clearance.[6,43] Oxidative stress and inflammation in the brain may aggravate nervous system dysfunction.[27,28] When pregnant mice were exposed to BPA at a concentration of 200 μg · kg−1 · day−1, at gestational day 15.5, fetal mice exhibited significantly increased numbers of microglia in the dorsal telencephalon and hypothalamus, up-regulated TNF-α and interleukin (IL)-4 mRNA, and increased M1 and M2 microglial markers were also detected. It has been suggested that embryonic exposure to BPA may affect not only the development of microglia but also the baseline inflammatory response of the brain.[44] In the brain of male mice exposed to 400 μg · kg−1 · bw−1 BPA for 60 days, reactive oxygen species (ROS) and xanthine peroxidase activity were increased. The pro-inflammatory cytokines IL-17, TNF-α, IL-1β, IL-12p40, and IL-6 were upregulated, while anti-inflammatory cytokine IL-10 was downregulated, and both the mature and immature oligodendrocytes showed degeneration changes.[45] Increased ɣH2AX phosphorylation in the dentate gyrus of rats exposed to BPA in embryo development and lactation was associated with genotoxicity and increased inflammatory response in hippocampal astrocytes, which may be related to the decreased ERα expression induced by BPA.[46] When adult male rats were exposed to 0.5 mg/kg or 5 mg/kg BPA for 4 weeks, lipid peroxidation in the cerebral cortex was significantly higher than for the control group.[47] The free radical-scavenging activity was decreased in the adult mice exposed to high concentration BPA, oxidative damage in the hippocampus was increased, and the ratio of oxidized DJ-1 (oxDJ-1)/DJ-1 and p-Akt/Akt was abnormal.[33] It has been demonstrated that both embryonic BPA exposure and direct BPA exposure after birth can result in local oxidative stress in the brain and induce the expression of inflammatory factors. In the above studies, BPA exceeded 50 μg · kg−1 · bw−1 of daily tolerable intake (TDI), reaching 4–10 times, although BPA dosage close to TDI could also increase microglia in the dorsal telencephalon of fetal rats;[44] however, for the embryonic exposure and subacute adult exposure, although the inflammatory factors showed a certain increasing tendency, there were no significant changes compared with the control. At present, it is not clear whether exposure to BPA at a concentration below the TDI causes an inflammatory reaction in the brain, nor is it known whether a non-monotonic relationship exists, similar to that observed in nerve cells, but exposure to higher concentrations of BPA did not affect lipid peroxidation in the adult rat brain.[47] Estrogen can play an inhibitory role in the inflammatory status of the brain.[48] In the aforementioned studies, only male animals were used for direct postnatal BPA exposure experiments, the inflammation of the brain induced by BPA in female animals, as well as in elderly animals with remarkably decreased estrogen, is not clear. However, no gender differences were observed with respect to the increases in microglia number induced by indirect embryonic BPA exposure.
BPA interfered with neural development and induced neuronal apoptosis, which was involved with abnormal cell metabolism, oxidative stress, and calcium overload in the in vitro studies. After 14 days of exposure to 0.1 μmol/L, 1 μmol/L, or 10 μmol/L BPA, human embryonic stem cell-derived human cortical neurons showed abnormal degradation in neurite outgrowth and increased apoptotic cells, accompanied by decreased microtubule-associated protein 2 (MAP2), increased intracellular ROS and enhanced calcium influx. Furthermore, these effects were BPA concentration-dependent. N-methyl-d-aspartate receptor antagonist could inhibit BPA-induced neuronal apoptosis, suggesting that the abnormal neuronal development and apoptosis induced by BPA are related to an imbalance in intracellular ROS and Ca2+ concentration.[49] Nanomolar BPA had been shown to increase the concentration of Ca2+ in rat hippocampal neurons through NMDA receptors, and this process was also involved with ERRγ-mediated ERKs and p38 signaling.[50] In addition, BPA increased concentrations of Ca2+ and ROS in SH-SY5Y neuronal cells.[36] Exposure to 100–200 μmol/L BPA inhibited proliferation of mouse Neuron-2a neuronal cells, disrupted synapses, and decreased the actin filament-binding protein drebrin, the microtubule-associated proteins MAP2 and tau protein [Figure 3].[51]
Figure 3: The mechanisms related to neural damage induced by BPA. BPA induced energy metabolism disorders by abnormal p-IR/p-IRS1 and decreased GLUT 1 and 3 in the hippocampus, calcium overload through NMDAR, and ROS increase in neuronal cells and glial cells. BPA resulted in activation of glia cells, leading to increased pro-inflammatory cytokines, and inflammatory factors promoted local inflammation, synergistically increasing brain dysfunction. BPA: Bisphenol A; GLUT: Glucose transporter; IL: Interleukin; IR: Insulin receptor; IRS: insulin receptor substrate; NMDAR: N-methyl-d-aspartate receptor; ROS: Reactive oxygen species; TNF-α: Tumor necrosis factor-α.
Therefore, embryonic exposure to BPA affected the development of neuronal cells and glial cells, and postnatal exposure to BPA, as well as cellular experiments, suggested that BPA induced oxidative stress, intracellular calcium overload or abnormal energy metabolism in neuronal cells and tissues, leading to abnormal morphological and functional changes and neuronal cell apoptosis. At the same time, increased expression of inflammatory factors promoted local inflammation, synergistically increasing brain dysfunction.
Gender and Nervous System Effects of BPA
The effects of BPA on the structure and function of the nervous system showed gender differences,[22,52] with similar tendencies observed in prenatal, perinatal, and postnatal exposure [Table 1]. In rats exposed to BPA before birth, cognitive disorder and spatial memory abnormalities were observed in both sexes, while passive avoidance memory impairments occurred only in male offspring.[13] In mice, exposure to BPA (0.5 μg · kg−1 · bw−1) from the beginning of pregnancy to postnatal day 21 caused learning and memory impairment only in male offspring, with no significant abnormalities observed in female.[15] Neurons within the hippocampal CA1 were more sensitive to BPA in male animals than those in female animals. Maternal exposure to 1 mg/L BPA could result in decreased hippocampal neuron number in male offspring, while the hippocampal neuronal abnormalities in female could be observed only with maternal exposure to 10 mg/L BPA. In addition, decreased p-NR2B protein was more obvious in the hippocampal neurons of male offspring than those of female.[13] Maternal exposure to 0.5 μg · kg−1 · bw−1 BPA could induce DNA damage in the hippocampal neurons of male offspring, while a concentration of 50 μg · kg−1 · bw−1 BPA induced similar DNA damage in female offspring.[15] Although there was no significant changes in neuron number for male offspring of the first generation, both dendritic length and spine density were decreased, with these effects persisting into the second generation, and the number of CA1 neurons decreased in the second generation; For female offspring, there was no significant change in dendritic length or spine density in the first and second generation.[15] In addition, GABA and 5-HT were increased in male, while Glu, Ach, and DA did not change significantly; female offspring of the first generation showed decreased Glu/GABA, increased Glu, GABA, 5-HT and DA, and unchanged Ach. Neurotransmitter changes occurred in males exposed to medium concentrations of BPA and in females exposed to low concentrations of BPA.[15] The downregulation of BDNF and CYP19A1mRNA induced by prenatal exposure to BPA occurs only in male offspring, but upregulation was shown in female offspring. Phosphorylated mitogen-activated protein kinase kinase (p-MEK), Phosphorylated protein kinase B (p-AKT), and phosphorylated extracellular signal-regulated kinase (p-ERK) were also shown to be increased in males and decreased in females.[19] The explanation for these gender differences in the effects of BPA on brain development-related neurotrophic factors and their downstream signal molecules is currently unclear, but may be related to the interference of BPA on estrogen receptors and downstream signaling.
Reduced dendritic spines and morphological changes were observed in the hippocampal CA1 and dentate gyrus neurons of rats subjected to intraperitoneal injection of BPA at concentrations of 0.5 μg · kg−1 · bw−1, 50 μg · kg−1 · bw−1, and 5000 μg · kg−1 · bw−1 from postnatal day 7–21. While all tested concentrations of BPA affected males, females were primarily affected by BPA at low and high concentrations, and the effects of moderate BPA concentrations were not significant. Male rats exposed to low and high concentrations of BPA were characterized by increased Glu and Glu/GABA ratio, and decreased 5-HT in the hippocampus, consistent with the loss of spatial learning and memory induced by BPA exposure. Low concentrations of BPA had no significant effects on hippocampal neurotransmitters in female rats, although medium concentrations of BPA did affect the previously mentioned neurotransmitters, but no significant changes were observed at dendritic density or dendritic spines, nor were spatial learning and memory ability affected in female rats, which may be related to endogenous estrogen.[14] Six-week-old adolescent rats were exposed to BPA (40 μg · kg−1 · bw−1) for 1 week, 7 weeks, or 11 weeks, the density of basal dendritic spines of pyramidal cells in the medial prefrontal cortex decreased more significantly in males than that in females. Impairments to non-spatial memory and object recognition were only observed in adult male rats, suggesting that the response of the medial prefrontal cortex to BPA is also affected by gender.[14,25] These results suggest that female animals were more tolerant to BPA than male animals. However, when female rats were ovariectomized 21 days after birth, then subcutaneously injected with 40 μg · kg−1 · bw−1 · day−1 BPA for 12 days (postnatal day 38 to 49), at puberty, these rats showed impaired spatial memory of object placement, reduced dendritic spines in the dentate gyrus and fewer neurons in the medial prefrontal lobe; spatial memory functions, including object placement and object recognition, were reduced in adulthood, and the reduction in dendritic spines was shown to extend to the hippocampal CA1 based on adolescent involvement.[53] After the removal of endogenous estrogen, female animals became more susceptible to BPA, suggesting that endogenous estrogen may protect the nervous system from abnormalities caused by BPA.
Other studies have implicated that the effects of BPA on neurons in the hippocampus and dentate gyrus are gender independent. After 8 weeks of exposure to 0.15 mg · kg−1 · day−1 or 7.50 mg · kg−1 · day−1 BPA, the density and morphology of dendritic spines decreased in the hippocampal CA1 region and the dentate gyrus, as did the Arc protein, which was closely related to the number and morphology of dendritic spines, however, no gender differences were observed in these changes.[18] BPA exposure reduced dendritic spine density in the hippocampal CA1 area and the medial prefrontal cortex of 6-week-old rats, and the results for female rats were similar to those for males.[16,25] In addition, juvenile Vervet monkeys were exposed to BPA for 30 days, such that the serum concentration was maintained at about 10 ng/mL. No effects on the synapses of pyramidal cells in the hippocampal CA1 and the dorsolateral prefrontal lobe were founded, and no cognitive impairments were detected. Moreover, no sex-specific effects were identified.
The correlation between gender and BPA effects on nerve tissue may be related to many factors, including start time or duration of the exposure, BPA concentration and method of administration, the particular brain regions and types of neuronal cells involved, as diverse sex hormones and their receptors may exist in the brains of different sex animals.[54] Further researches will be necessary to determine whether gender differences exist with regard to neuronal BPA response in different brain regions, especially the hippocampal CA1 and CA3, the dentate gyrus, the medial and the dorsolateral prefrontal lobe, as well as to assess whether gender plays a role in modulating the effects of BPA exposure at different developmental stages.
Effects of BPA Analogs on the Nervous System
With the increasing use of BPA substitutes, their effects on the brain and neuronal cells have been noticed widely.[55] BPAF, BPS, and bisphenol B (BPB) have been shown to induce apoptosis in HT-22 hippocampal neurons and primary mouse neuronal cells. The mechanisms included calcium overload, increased ROS production, and P38 and JNK protein phosphorylation.[56,57] Prenatal or early postnatal exposure to both BPF and BPS affected 5α-reductase3 (5α-R3) in the prefrontal lobe, and the genes related to dopamine and 5-HT.[58] Zebrafish studies have shown that exposure to BPA analogs at different developmental stages can lead to oxidative stress, which affects nervous system function by disrupting brain development, dysregulating neurotransmitter secretion, and inducing neuronal cell apoptosis. While zebrafish fetuses exposed to BPF at environmental concentrations were marked by apoptotic central nervous system cells and activation of microglia and astrocytes, but the neurotransmitters of 5-HT, dopamine, and Ach were unaffected.[59] When juvenile zebrafish were exposed to BPF at a dosage corresponding to 1/100–1/10 of median lethal concentration (LC50), increased apoptotic cells were detected in the brain, accompanied by decreased expression of α1-tubulin and glial fibrillary acidic protein (GFAP). In addition, decreased activity of antioxidant enzymes catalase (CAT) and super oxide dismutase (SOD) and increased malonaldehyde (MDA) production were also found. These results suggested that BPF induced oxidative stress in the zebrafish brain and disturbed brain development. Although exposure to 7 μg/L of BPF, equivalent to 1/1000 LC50, had no significant effects on neurodevelopment, but was associated with reduced antioxidant enzyme activity in the zebrafish brain.[60] Furthermore, lower concentrations of BPF (0.5 μg/L) induced microglia and astrocytes activation as well as TNF-α upregulation in the zebrafish brain, suggesting that BPF may cause brain injury by inducing an inflammatory response.[59] In adult zebrafish, chronic exposure to BPS at the concentration of 10 μg/L and 30 μg/L for 120 days resulted in abnormal recognition memory, and glutamate receptor, ERK1/2, and CREB protein were also decreased.[61] After exposure to the same concentration of BPS for 75 days, glutathione peroxidase, Cu/Zn-SOD, and CAT were downregulated, which indicated abnormal antioxidant capacity induced by BPS.[62] At present, BPA substitutes have been demonstrated to have relatively little effects on the nervous system [Figure 4], however, considering the increasing use of these substitutes and their presence detected in the human body, the possible adverse effects of BPA analogs deserve further investigation.
Figure 4: Neural disorders induced by BPA analogs. BPA analogs cause calcium overload, increase ROS products, decrease the ability of CAT and SOD, induce neuron apoptosis, likewise induce the activation of microglia and astrocytes. BPA: Bisphenol A; BPF: Bisphenol F; BPS: Bisphenol S; CAT: Catalase; ROS: Reactive oxygen species; SOD: Super oxide dismutase; TNF-α: Tumor necrosis factor-α.
Conclusion
In summary, both in vivo and in vitro studies suggest that BPA and its analogs have effects on the central nervous system. Prenatal exposure may disturb neural development, while postnatal exposure can damage nerve tissue and neuronal cells. Neurons in the hippocampus, dentate gyrus, and prefrontal cortex are susceptible to BPA of both prenatal and postnatal exposure, highlighting the relationship between bisphenols and neurodegenerative diseases, such as AD and PD. In addition, gender differences may exist with respect to the effects of BPA on the nervous system, and males are typically more sensitive than females, which may be related to different levels of estrogen. Insufficient evidence exists to determine whether the changes to the nervous system induced by prenatal bisphenol exposure persist through the second generation. Moreover, sex hormones decrease with aging, as does the ability to protect nerve tissue and cells. On this basis, it is critical to determine whether chronic exposure to bisphenols aggravates damage to nerve tissue.
Funding
The work was supported by a grant from the National Natural Science Foundation of China (No. 21577095).
Conflicts of interests
None.
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