IMR Press / FBL / Volume 26 / Issue 2 / DOI: 10.2741/4897

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Open Access Review
Bisphenol A: an endocrine-disruptor compound that modulates the immune response to infections
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1 Departamento de Parasitologia, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autonoma de Mexico, CP 04510, Ciudad de Mexico, Mexico
2 Departamento de Farmacologia, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, CP 04510, Ciudad de Mexico, Mexico
3 Laboratorio de Genotoxicología y Mutagenesis Ambiental, Departamento de Ciencias Ambientales, Centro de Ciencias de la Atmosfera, Universidad Nacional Autonoma de Mexico CP 04510, Ciudad de Mexico, Mexico
4 Unidad de Investigacion Medica en Enfermedades Infecciosas y Parasitarias, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, 06720, Cd de Mexico, Mexico
5 UIM en Inmunologìa, Hospital de Pediatrìa, CMN S XXI, IMSS, 06720, Cd de Mèxico, Mexico
6 Departamento de Inmunologìa, Instituto de Investigaciones Biomedicas, Universidad Nacional Autònoma de Mèxico, 04510, Cd de Mexico, Mexico
Front. Biosci. (Landmark Ed) 2021 , 26(2), 346–362; https://doi.org/10.2741/4897
Published: 1 October 2020
(This article belongs to the Special Issue Enviromental medicine and its impact on human health)
Abstract

Bisphenol A (BPA) is an endocrine-disruptor compound that exhibits estrogenic activity. BPA is used in the production of materials such as polycarbonate plastics, epoxy resins and dental sealants. Whereas, the endocrine modulating activity of BPA and its effects on reproductive health have been widely studied, its effects on the function of the immune system are poorly characterized. This might be attributable to the different BPA doses used in a diversity of animal models. Moreover, most studies of the effect of BPA on the immune response are limited to in vitro and in vivo studies that have focused primarily on the impact of BPA on the number and proportion of immune cell populations, without evaluating its effects on immune function in response to an antigenic challenge or infectious pathogens. In this review, we discuss the current literature on the effects of BPA on the function of immune system that potentially increases the susceptibility to infections by the virtue of acting as a pro-inflammatory molecule. Thus, it appears that BPA, while by such an impact might be useful in the control of certain disease states that are helped by an inflmmatory response, it can worsen the prognosis of diseases that are adversely affected by inflammation.

Keywords
Review
Environmental pollution
Environmental medicine
Endocrine disruptors
Bisphenol A
Immunoregulation
Infection
Review
2. ENDOCRINE DISRUPTING COMPOUNDS (EDCS)

Endocrine disrupting compounds (EDCs) are substances that exist in the environment as a result of agricultural and industrial activity. Some examples are dichlorodiphenyltrichloroethane (DDT), Bisphenol A (BPA), Bisphenol S (BPS), phthalates, among others, but they also can be found in pharmaceutical products (ethinylestradiol, diethylstilbestrol (DES)) or naturally in different plants such as soybean (phytoestrogens, genistein, daidzein, coumestrol) (Figure 1). EDCs may exhibit estrogenic, anti-estrogenic or anti-androgenic activity. In addition, these compounds are highly lipophilic and can be stored for prolonged periods of time in the adipose tissues. During pregnancy, the fetus can be exposed to these compounds through the placenta and at birth by the lactogenic route (1, 2).

Figure 1

Chemical structure of several EDCs. a) Synthetic origin; Dichloro-Diphenyl-Trichloroethane (DDT), Bisphenol A (BPA), Bisphenol S (BPS), Tetrabromo Bisphenol A (TetrabromoBPA), Ethinylestradiol, Diethylstilbestrol (DES). b) Natural origin; Genistein, Coumestrol, Daidzein.

3. BISPHENOL A (BPA)

BPA is widely used as a monomer in the production of polycarbonate plastics, epoxy resins and dental sealants (4). This compound can be released easily from these materials due to incomplete polymerization or hydrolysis of the polymers that contain it, which can occur when they are exposed to high temperatures, acidic conditions or enzymatic process. The main BPA exposure source in animals and humans is through out food and beverages that have been in contact with materials manufactured with BPA, which is detached from its matrix and it is ingested orally (5). BPA is classified as an EDC with estrogenic character since it can bind to nuclear estrogen receptors (ERα and ERβ) and trigger signaling pathways, even when its affinity is lower (<1,000) than the endogenous ligand, 17β-estradiol (Figure 2) (6). In addition, BPA also binds to the estrogen like G-coupled protein receptor (GPER), the estrogen related receptor gamma (ERRγ), the arylhydrocarbon receptor (AhR) (7), the thyroid hormone receptor (ThR) (8), the peroxisome proliferator-activated receptor gamma (PPARγ) (9), the glucocorticoid receptor and the thyroid hormone receptor (TR) (8–15). Despite the Food and Drug Administration (FDA) and the European Food Safety Agency (EFSA) calculated that the Tolerable Daily Intake of BPA is 50 μg / kg / day, it has been estimated that exposure to BPA per food package is 0.185 μg / kg / day in adults and up to 2.42 μg / kg / day in children from 1 to 2 months of age (8). Besides, it has been demonstrated that BPA exposure at the tolerable concentrations or below is related to negative effects in the health of both, humans and rodents (13, 16, 17).

Figure 2

Schematic representation of E2 and BPA interaction with nuclear ERs. E2 or BPA interacts with nuclear ERs. BPA; Bisphenol A, E2; Estradiol; ERα or β; Estrogen receptor alpha or beta. The interaction between BPA and ER will activate genes such as ERK and NFκB, which will generate the production of proinflammatory cytokines and nitric oxide. BPA; Bisphenol A, E2; Estradiol, ER; Estrogen Receptor, ERK; extracellular signal-regulated kinases; NFκB; nuclear factor kappa-light-chain-enhancer of activated B cells, NO; Nitric Oxide.

4. BPA EFFECTS ON THE IMMUNE SYSTEM

Different BPA effects have been reported on the immune system cells; however, they vary depending on whether they were performed as in vivo or in vitro. In vivo, the effects reported may seem contradictories, but they are not, since the reported effects depend on the animal species used, the dose, the administration route, the sex of the animal, the age, and the animal’s development stage in which BPA is administered. Furthermore, many reports do not consider that the immune response must be studied by challenging the immune components, so there is little information about the BPA effects on the immune response during an infectious process. In the next paragraphs, we summarize the reported BPA effect on all the immune cells reported to date. To make it more comprehensive, we divide them in innate and adaptive immune cells (Figure 3).

Figure 3

Effects of BPA on the cells of the immune system. The BPA effects in different immune cells are variable depending on the type of model, in vivo or in vitro, the animal species used, the dose, the administration route and the stage of development in which it is administered. Mo; Macrophages, DC; Dendritic cells, Eos; Eosinophils, No; Neutrophils, PC; Plasma cells, BL; B lymphocytes, ThL; T helper lymphocytes, Treg; T regulatory lymphocytes

4.1. BPA effects on innate immune cells
4.1.1. Macrophages

Macrophages are one of the main phagocytic cells that play an important role in the maintenance of organism homeostasis. Furthermore, they express the two ER isoforms (ERα and ERβ) whereby BPA could exert its effects (18, 19). On line with that, different studies have evaluated the BPA stimulatory effects on macrophages. Hong et al. (2004) reported that BPA at a concentration of 43 nM potentiated nitric oxide production (NO) in a murine macrophage cell line (RAW264), after lipopolysaccharide (LPS) exposure; while interferon-gamma (IFN-γ) production was not altered (20). Other experiments developed by Yamashita et al. (2005) described that BPA at a concentration of 0.1 μM stimulated pro-inflammatory cytokines production such as IL-1, IL-6 and IL-12, also BPA treatment increased the co-stimulatory molecule CD86 expression in murine peritoneal macrophages (21). In concordance with this study, mouse peritoneal macrophages under M1 type conditions that were exposed to low concentrations of BPA (> 1 μM) promotes polarization toward M1 subtype by the upregulation of IRF5 expression, as well as TNF-α, IL-6 and MOP-1; while the same BPA exposure to macrophages under M2 type conditions inhibits the M2 subtype polarization by the downregulation of IL-10 and TGF-β (22). In addition, a BPA analog (BPA-glycidyl-methacrylate (BisGMA)) stimulated Tumor Necrosis Factor alpha (TNF-α) production with a concomitant increase of surface molecules (CD11, CD14, CD40, CD45, CD54 and CD80) expression on a macrophage cell line (RAW264.7). Like BPA, the BisGMA induced the production of IL-1β, IL-6, and NO, as well as the inducible nitric oxide synthase (iNOS) expression and raised the generation of reactive oxygen species (ROS) intra and extracellular in a dose-dependent manner (23).

The increment of IL-6 and TNF-α secretion stimulated by BPA (0.1 μM) was also observed in a human macrophage cell line (THP1), on the contrary, secretion of regulatory cytokines such as IL-10 and TGF-β was decreased by BPA treatment. Moreover, the treatment of an ER antagonist (ICI 182,780) reversed this cytokine production pattern, indicating that BPA effects are carried out by its binding to ERs (24). Interestingly, BPA can induce alternative macrophages activation (M2), reducing IL-6, IL-10 and IL-1β production in macrophages derived from human peripheral blood monocytes (PBMCs), stimulated or not with LPS or IL-4. This work also reported that BPA treatment increased the IL-10 and decreased the IL-6 production in macrophages classically activated (M1) (25). Finally, a work of Yang et al. (2015) reported that BPA increased the production of NO and ROS in a dose-dependent manner in carp (Cyprinus carpio) macrophages (26).

On the other hand, inhibitory BPA effects on macrophages function have also been reported. Segura et al. (1999) evaluated the adhesion capacity of the peritoneal macrophages of rats after BPA treatment, this compound (10 nM) inhibited the macrophages adherence but it did not have effect on their viability (27). In another study, Kim and Jeong (2003) evaluated the effect of BPA on the production of NO, TNF-α and iNOS expression in mice peritoneal macrophages. BPA (50 μM) did not affect the NO and TNF-α production. On the contrary, when LPS was used as stimuli, BPA treatment inhibited their production. In addition, BPA decreased the iNOS expression in a dose-effect dependent manner (28). Supporting this fact, Byun et al. (2005) indicated that mice peritoneal macrophages, obtained from mice injected with BPA (500 mg / kg / day) for 5 consecutive days during 4 weeks, and cultured ex vivo with LPS, had a marked reduction in TNF-α and NO production. A similar effect was observed in a macrophage culture treated with BPA (10 and 100 Μm) (29). The BPA cell inhibitory effect was also observed in RAW 264 macrophage cell line, where BPA exposure (100μM) inhibited IFN-β promoter activation after LPS stimulation (30). Moreover, this estrogenic compound also suppressed the NO production and NFƙB activation in the same cell line with the same stimulus. Of note, these effects were blocked by the estrogen receptor antagonist ICI182,780 (31). In line with that, BPA (200 μM) exposure in RAW 264.7 macrophage cell line also shown to inhibit the production of NO and induce apoptosis cell death (32). In summary, BPA alters macrophage functions by decreasing cytokine secretion, activating of M2 phenotype and stimulate the expression of adhesion molecules.

Finally, in a recent study Liu et al (2020), report that BPA (100 μg / L) generates immunotoxicity in macrophages from common carp (Cyprinus carpio), by increasing the expression of long non-coding RNAs (33). This is reflected in the alteration of some signaling pathways related to the immune response, such as: NF-κ B, Toll-like receptor, B-cell receptor and the Jak-STAT signalling pathway (33).

4.1.2. Dendritic cells

Dendritic cells (DCs) are the par excellence antigen presenting cells; they play a fundamental role in the begining of the immunological response and its polarization and regulation. It has been reported that these cells also express ERα and Erβ (34). Limited studies have investigated the BPA effects on DCs. Guo Y and cols. (2010), reported that treatment of BPA in DCs derived from PBMCs increased the chemokine ligand 1 (CCL1) expression, the IL-5, IL-10 and IL-13 production as well as the expression of the transcription factor GATA3 in the presence of TNF-α (35), demonstrating that the exposure to BPA alters the functions of human DCs by inducing preferentially a Th2 response. Furthermore, BPA affected DCs differentiation by increasing the class II major histocompatibility complex (MHC II) and CD69 expression (36). On the other hand, Švajger et al. (2016), indicated that BPA at a concentration of 50 μM decreased the DCs endocytic capacity as well as the CD1a expression (an important protein mediating antigenic presentation) (37). BPA at low concentrations (1 nM) also increased the DCs density, however, the expression of DCs activation markers (HLA-DR and CD86) was decreased in human DCs derived from PMBCs (38). BPA had no effect neither in cultivated bone marrow precursors or in the proliferation of the DCs, regardles of concentration (39). The works previously described suggest that exposure to BPA affects human DCs function in a concentration dependent manner.

4.1.3. Granulocytes

Granulocytes are the most abundant innate immune cells. They are divided into neutrophils, which constitutes between 90 and 95% of their totality, eosinophils from 3 to 5% and basophils less than 1%. In the literature there are few reports about the BPA effect on these cells. In the case of neutrophils, Watanabe et al., (2003) evaluated the effect of BPA on the neutrophilic differentiation induced by dimethylsulfoxide (DMSO) and granulocyte colony stimulating factor (G-CSF) in a leukemia cell line (HL-60). Tthey reported that low doses of BPA (10-10 and 10-8 M) increased the expression of the CD18 integrin protein, the neutrophilic differentiation as well as superoxide production. Interestingly, the treatment with an estrogen receptor inhibitor (tamoxifen) in these cells, did not suppress the BPA effect, suggesting that all the effects above are mediated by an ER-independent pathway (40). Another BPA-related compound, tetrabromobisphenol A (TBBPA), also increased the ROS neutrophils production in a dose-dependent manner (41).

BPA exposure has also been found to affect eosinophils, which are key players in allergy and asthma pathogenesis. In vivo experiments, using mouse models of allergic asthma, described that perinatal BPA exposure enhanced eosinophilic inflammation and airway responsiveness (42), suggesting that BPA exposure can affect the disease during critical developmental periods. Similar results were observed when adult mice were sensitized with ovalbumin combined with BPA treatment, where the result of the treatment significantly increased eosinophil recruitment in the alveoli and submucosa of the airways and enhanced eosinophil-produced cytokine and chemokine levels (43). These studies suggest that early or late life exposure to BPA could enhance the severity of immune-mediated diseases such as allergic diseases and asthma.

4.1.4. Mast cells

Mast cells are resident tissue cells that play a key role in inflammatory and allergic processes (44). These cells are characterized by their high content of cytoplasmic granules containing preformed mediators that include the vasoactive amine histamine, proteases, as well as some cytokines (45). Mast cells may be activated by a variety of stimuli through the numerous receptors on their surface. Upon activation, mast cells can release preformed as well as a several distinct newly synthesized mediators (44,45). The most studied mechanism of mast cell activation is the IgE-mediated response, which can be divided into two stages; in the first stage, IgE produced by plasma cells binds to the FcɣRI on the mast cell surface, leading to a sensitized state. Later, upon a second encounter with the antigen, it can bind to the surface-binded IgE, which after crosslink of IgE triggers mast cell degranulation and release of mediators. Though BPA exposure has been linked to allergen sensitization, there is limited information concerning BPA effects on mast cell-response. In a two-generational study, O’Brien reported that perinatal BPA exposure through maternal diet (ranging from 50 ng to 50 mg / Kg diet) caused an increase in mast cell-derived leukotrienes, prostaglandin D2, TNF-α and IL-13, suggesting greater activation of these cells (46). Further studies will be needed to evaluate the role of the BPA exposure on mast cell response and its association to allergic diseases.

5. BPA EFFECTS ON ADAPTATIVE IMMUNE CELLS
5.1. T lymphocytes

T lymphocytes (TL) are cells of the adaptive immune system, they can be divided into cytotoxic T lymphocytes (CTLs) or T helper lymphocytes (ThL), which can differentiate into Th1, Th2, Th9, Th17, Th33., based on their secreting cytokines pattern. These cells express different hormone receptors (47), thus sex steroids can regulate the TLs differentiation and their response (48, 49). Some studies have reported that BPA exerts its effects through out the binding to them with a consequent modulation of TL response and polarization (Th1, Th2, and Th17).

In an ex vivo model, Youn et al., (2002) described that BPA induced cell proliferation in Concanavalin A (Con-A)-stimulated splenocytes derived from mice orally exposed to BPA during 4 weeks, with no in ThL, CTL subpopulation percentages. In addition, the IFN-γ and the IL-4 expression was induced and reduced, respectively (50). Moreover, in chicken egg lysozyme (HEL) model, Yoshino et al., (2003) reported that BPA significantly increased the IFN-γ and IL-4 secretion, suggesting that BPA promoted the Th1 response. This cytokine secretion pattern was also reported in prenatally BPA-exposed mice, after being immunized with HEL in the adulthood, however the Th1 cytokine changes observed were greater than the Th2 (51, 52). In accordance with this concept, Alizadeh et al., (2006) reported an increase in IL-12 and IFN-γ production on splenocytes derived from animals exposed to BPA in an OVA-induced allergy model (53). Coupled with this effect, Menard et al., (2014) evaluated the BPA effect on the specific immune response against the OVA antigen, they found that BPA increased the LTh percentages and the IFN-γ secretion (54). It is important to mention that the perinatal BPA exposure (day 9.5 of gestation until weaning), producedchanges in cytokine expression, such as G-CSF, GM-CSF, IL-12p70, IL-1α, IL-1β, TNF-α and Rantes at serum levels (55). Moreover, this cytokine secretion pattern together with the IL-4 and IL-6 increase was also observed in splenocytes previously stimulated with Con-A. Also, the supernatants of cultured splenocytes were evaluated and the GM-CSF, IFN-γ and IL-17 expression was also increased after LPS stimulus. All the above confirms that BPA impacts on Th1 cytokines with a bias towards a Th17 type response (55).

In mice, BPA exposure administrated in their drinking water during the perinatal period, increased the expression of the transcription factor RORγt, and the cytokines IL-17, IL-21, IL-6 and IL-23 in a dose-dependent manner, in both males and females. (56). This is <in agreement with previously reported data by Holladay et al., 2010. Some studies have reported that BPA was able to generate T cell polarization, directing it to a Th2 response. With respect to this statement, in an in vitro model, lymphocytes exposed to BPA showed an induction of the GATA-3, IL-4 and IL-10 expression and a reduction of the T-box transcription factor (Tbet) expression, suggesting an induction of Th2 polarization (57). Similar effects were reported in activated T lymphocytes with respect to IL-4 expression (58).

Additionally, Miao et al., (2008), using a gestational exposure scheme, reports that exposure to BPA generates a decrease in ERα expression in males, while the expression of this receptor is increased in females and the expression of Th1 cytokines (IL-2, IL-12, IFN-γ and TNF-α) was decreased in both males and females (59). Sawai et al. (2003) in in vitro experiments on splenocytes stimulated with Con-A, reported that males exposed to BPA, produced on average 40% less IFN-γ while females 28% less compared to controls (60). Regarding on regulatory T cells (Tregs) Ohshima et al., (2007), reported that the perinatal administration of BPAgenerated a decrease in the Tregs number (61).

5.2. B lymphocytes and plasmatic cells

B lymphocytes (BL) are cells whose importance lies in humoral immunity, since they are able to differentiate into plasmatic cells (PCs), which are responsible for the production of antibodies such as IgA, IgG, IgE, IgD and IgM. In different studies, it has been observed that BPA may modify in a different way the production of antibodies by these cells. Yoshino et al., (2003) using male and female DBA / 1J adult mice, report that BPA generates an increase in the proliferation of splenocytes, in addition to an increase in the production of antibodies in a dose-dependent manner (51). Similarly, in another study, it was reported that gestational exposure to BPA generated increased production of IgG1 and IgG2a antibodies, with predominance of IgG2a antibodies in male offspring (52).

Menard et al. (2014), reported that in female rats exposed perinatally to BPA there is an increase in anti-OVA IgG antibodies during adult life (54). Alizadeh et al. (2006), indicate that exposure toBPA, in female BALB/c mice, generates lower IgE antibody titers and higher levels of IgG2a (53). Similarly, Lee et al. (2003), indicate that there is an increase in IgE in female BALB/c mice exposed to BPA during adult life (58). In another study, using young mice of the strain NZB/NZW (systemic lupus erythematosus murine model), which were exposed to BPA, and later in adult life thethe splenocytes were obtained and stimulated with LPS, there is a decrease in the production of IgG2a in splenocyte culture supernatants (60). Yurino et al. (2004), using BWF1 mice (another model of systemic lupus erythematosus), which were ovariectomized at four weeks of age, and that were subsequently implanted with subcutaneous implants of BPA during four months, reported that the exposure to BPA generates an increase in the production of anti-RBC IgM autoantibodies by B1 cells, as well as ERα expression both in vitro and in vivo (62). Moreover, Goto et al. (2007), administering BPA in the drinking water in male and female mice with transgenic TCR andstimulated with OVA reported an increase in the production of IgG2a and IgA in supernatants of splenocyte cultures from these mice (63). Finally, Midoro-Horiuti et al. (2010), using an asthma model in BALB/c mice, indicated that perinatal exposure of BPA in the drinking water, increases serum levels of anti-OVA IgG (42).

6. EFFECTS OF BPA ON INFECTIONS
6.1. Virus

So far, there is only one report about the effects of BPA in the virus infection context. Roy et al. (2012), evaluated the perinatal BPA exposure on the immune response associated with the infection of influenza A virus during adult life on a murine model (Table 1). The report indicated that the perinatal exposure to BPA did not affect the specific adaptive immune response against the influenza virus at the lung. However, this exposure to BPA temporarily reduced the lung inflammation associated to the infection- and also the expression of antiviral genes (IFN-γ and iNOS) in lung tissue: The study concluded that perinatal BPA exposure modulated the innate immune response in the adult mice, but not the adaptive response, which is fundamental for the elimination of the influenza virus (64).

Table 1 Effect of BPA on susceptibility to different infections
Pathogen Mode of administration Dose Effect Reference
Influenza A Perinatal 50 µg/kg/day Temporary reduction of the degree of pulmonary inflammation 64
Escherichia coli Prepuberal 5 mg/kg/day x 5 days Increase the number of colonies forming units 65
Leishmania major Adult 5.7, 11.4, 22.8 y 45.6 mg/kg one week before infection Increase susceptibility in a dose-dependent manner 68
Leishmania major Perinatal 1, 10 y 100 nM Increase susceptibility in a dose-dependent manner 68
Trichinella spiralis Adult 228 µg/mice Decreased susceptibility 69
Nippostrongylus brasiliensis Perinatal 5 µg/kg/day Increase susceptibility 44
Toxocara canis Perinatal 250 μg/kg/day Increase susceptibility 72
6.2. Bacteria

In the context of bacterial infections, BPA exposure, affected the defense against Escherichia coli (E. coli) in young mice (Table 1). BPA decreased the ability of immune cells to eliminate E. coli at 24 hrs post-infection. In addition, BPA induced neutrophil migration to the peritoneal cavity and reduced their phagocytic capacity against the bacteria Coupled with these effects, a reduction in macrophage and lymphocyte populations were also observed (65). Moreover, the analysis of bacteria number in the peritoneal cavity indicated that there was a greater number of Colony Forming Units (CFU) in animals exposed to BPA as compared with untreated group (65).

While not properly an infection, bacterial colonization of the gastrointestinal tract needs to keep a balance between symbiotic, commensal and pathogenic species and maintains a bidirectional relationship with the immune system. In recent years, the microbiome has gained attention, since it has been demonstrated that it can affect not only the intestinal health, but also the metabolism and even neurological phenomena. In that regard, BPA exposure has also been shown to alter the gut microbiome. Lai et al. (2016), found a significant reduction in gut microbiota diversity in mice exposed to BPA through out the diet. Interestingly, this effect is similar to that induced by high fat and high sucrose diets. Furthermore, this altered microbiota was enriched in proteobacteria, which it is a known as a marker of dysbiosis (66). Moreover, another group reported that the BPA effect on microbiome reaches the second generation of bacteria, and that some bacteria -associated disease such as Bacteroides,Mollicutes,Prevotellaceae,Erysipelotrichaceae,Akkermansia,Methanobrevibacter and Sutterella increase in proportion in BPA trteated animals (67).

6.3. Parasites

The BPA effect upon immune response against Leishmania major (L. major) infection has been reported. In this context, the prenatal (administration of BPAin the drinking water, two weeks before mating and one-week post-mating,or in the adult lifeone week before to infection with L. major) induced an increase in the inflammation in the food pad of mice in a dose-dependent manner inr L. major infected mice (Table 1). The Treg cells number was also reduced at splenic level in both, mice exposed to BPA at prenatally or in the adult stage. Of note, animals exposed to BPA in the adult stage have an IL-4, IL-10 and IL-13 increased level expression after L. major infection. Similar effect was reported in animals exposed to BPA prenataly where an IL-4 and IFN-γ increase was found (68). BPA effect in Trichinella spiralis (T. spiralis) infection has also been reported. The model was performed in mice exposed to a single dose (228 µg per mice) of this compound after 22 hours of T. spiralis infection, then mice were sacrificed at 42 days post infection and the muscle larvae number were counted. The study reported that BPA decreased the larvae number, suggesting that BPA has a protective effect against to this nematode infection (69). Recently, we have demonstrated that neonatal (3 days of age)) male and female syngeneic BALB/c mice exposed to a single dose of BPA, and that further were infected with the human nematode Trichinella spiralis in the adulthood, harbour fewer parasitic loads on the duodenum. Protective effect of BPA was related to an immunomodulatory effect of BPA related to the specific immune response to the helminth (70). Similarly, Nava-Castro et al (2020) demonstrated that neonatal treatment with a single dose of BPA, decreases parasites loads in the adulthood in BalB/c female mice intraperitoneally infected with the helminth parasite Tania crassiceps. Also, in this case, BPA had an specific immunomodulatory effect on the immune response (71). On the contrary, Ménard et al. (2014), using a perinatal administration model (day 15 of pregnancy until day 21 postnatal) of BPA in rats, administered in their drinking water and infecting afterwards with the parasite Nippostrongylus brasiliensis (N. brasiliensis), reported an increase in susceptibility to infection in young female offspring (25 days of age) that were exposed to BPA perinatally (44). Similarly, Del Río et al. (2020), report an increase in susceptibility to Toxocara canis (T. canis) infection in adult male rats exposed perinatally (day 5 of gestation at 21 days postnatal) at a dose of 250 μg / Kg / day of BPA. The increase in larvae number was related to an inadequate polarization of the immune response, where there was an increase in Th1 cytokines TNF-α and IFN-γ, while there was a decrease in Th2 cytokines IL-4 and Il-5, as well as specific anti-T. canis IgG antibodies (72).

As for the direct effects exerted by BPA on parasites, Tan et al. (2015), reported that this estrogenic compound increased mortalityof Caenorhabditis elegans (C. elegans), also BPA accelerated its aging process by increasing mitochondrial and cytosolic oxidative stress, as well as ROS generation (73). Other report indicated that BPA exposure at concentrations of 1 to 10 μM on C. elegans embryos decreased the parasites´ oviposition during adult life (74). On the other hand, Zhou et al. (2016), in a multigenerational study using C. elegans as a model, reported that BPA induced physiological changes over the four generations of parasites, depending on the EDC concentration exposure (0.001-10 µM). In the first generation, parasites had a lower growth, moved slowly and produced lower offspring than nematodes that were not exposed to BPA (75). This work also referred that long-term BPA exposure (10 days), generated chronic toxicity affecting physiological indicators as body size, head contractions, body curvature and half-life; coupled with a greater stress response and a decrease in the population size (76).

7. CONCLUSIONS

Endocrine disrupting compounds modulate endogenous steroid responses and cell functions. Although most studies focus on their reproductive effects, their potential effects on immune cells and even more, on the immune response towards pathogens, should draw attention, given the expression of hormonal receptors by immune cells. Despite the fact that a lot of studies have evaluated the BPA effect with different variables such as BPA concentration, type of model, administered BPA dose, life stage or antigenic challenge used, one common element remains: BPA can differentially modulate the immune response. Sometimes, BPA treatment helps the host to defend it self against a pathogen, sometimes BPA treatment it is detrimental and helps the invader. Thus, BPA not always has to be considered an enemy, but a double edge sword, that depending on the context of the However, more studies are needed with the aim to elucidate the possible mechanisms by which this takes place.

8. ACKNOWLEDGMENTS

Financial support: Grant IN-209719 from Programa de Apoyo a Proyectos de Innovación Tecnológica (PAPIIT), Dirección General de Asuntos del Personal Académico (DGAPA), Universidad Nacional Autónoma de México (UNAM) and Grant FC2016-2125 from Fronteras en la Ciencia, Consejo Nacional de Ciencia y Tecnología (CONACYT), both to Jorge Morales-Montor. Grant IA 206220 to Víctor H del Río Araiza, from PAPIIT, DGAPA, UNAM. Grant IA 202919 to Karen Elizabeth Nava-Castro, also from PAPIIT, DGAPA, UNAM. Carmen T. Gómez de León is a recipient of a Post-Doctoral fellowship from Grant FC2016-2125, Fronteras en la Ciencia, Consejo Nacional de Ciencia y Tecnología (CONACYT).

References
[1]
Guzmán-Arriaga C Zambrano E Endocrine disruptor compounds and their role in the developmental programming of the reproductive axis. Rev Investig Clin 2007 59 73 81
[2]
PergialiotisV KotrogianniP Christopoulos-TimogiannakisE KoutakiD DaskalakisG PapantoniouN Bisphenol A and adverse pregnancy outcomes: a systematic review of the literature. J Matern Fetal Neonatal Med20183133203327DOI: 10.1080/14767058.2017.1368076 PMid:28805116
[3]
SweeneyT Is exposure to endocrine disrupting compounds during fetal/post-natal development affecting the reproductive potential of farm animals? Domest Anim Endocrinol200223203209DOI: 10.1016/S0739-7240(02)00157-1
[4]
MendesJJ Amaral The endocrine disrupters: A major medical challenge. Food Chem Toxicol200240781788DOI: 10.1016/S0278-6915(02)00018-2
[5]
WelshonsW V NagelSC SaalFS Vom Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure. Endocrinology20061475669DOI: 10.1210/en.2005-1159 PMid:16690810
[6]
KuiperGG LemmenJG CarlssonB CortonJC SafeSH SaagPT van der BurgB van der aJ Gustafsson. Interaction of estrogenic chemicals and pytoestrogens with estrogen receptor beta. Endocrinology199813942524263DOI: 10.1210/endo.139.10.6216 PMid:9751507
[7]
Bonefeld-JørgensenEC LongM HofmeisterM V VinggaardAM Endocrine-disrupting potential of Bisphenol A, Bisphenol A dimethacrylate, 4-n-nonylphenol, and 4-n-octylphenolin vitro: New data and a brief review. Environ Health Perspect20071156976DOI: 10.1289/ehp.9368 PMid:18174953 PMCid:PMC2174402
[8]
Pogrmic-MajkicK KosaninG NenadovD Samardzija FaS StanicB PjevicA Trninic AndricN Rosiglitazone increases expression of steroidogenic acute regulatory protein and progesterone production through PPARγ-EGFR-ERK1/2 in human cumulus granulosa cells. Reprod Fertil Dev20193116471656DOI: 10.1071/RD19108 PMid:31233701
[9]
SargisRM JohnsonDN ChoudhuryRA BradyMJ Environmental endocrine disruptors promote adipogenesis in the 3T3-L1 cell line through glucocorticoid receptor activation. Obesity (Silver Spring)20101812838DOI: 10.1038/oby.2009.419 PMid:19927138 PMCid:PMC3957336
[10]
MoriyamaK TagamiT AkamizuT UsuiT SaijoM KanamotoN HatayaY ShimatsuA KuzuyaH NakaoK Thyroid hormone action is disrupted by bisphenol A as an antagonist. J Clin Endocrinol Metab200287518590DOI: 10.1210/jc.2002-020209 PMid:12414890
[11]
WetherillYB AkingbemiBT KannoJ McLachlanJA NadalA SonnenscheinC WatsonCS ZoellerRT BelcherSM In vitro molecular mechanisms of bisphenol A action. Reprod Toxicol200724178198DOI: 10.1016/j.reprotox.2007.05.010 PMid:17628395
[12]
Alonso-MagdalenaP RoperoAB SorianoS García-ArévaloM RipollC FuentesE QuesadaI NadalÁ Bisphenol-A acts as a potent estrogen via non-classical estrogen triggered pathways. Mol Cell Endocrinol2012355201207DOI: 10.1016/j.mce.2011.12.012 PMid:22227557
[13]
RochesterJR Bisphenol A and human health: A review of the literature. Reprod Toxicol201342132155DOI: 10.1016/j.reprotox.2013.08.008 PMid:23994667
[14]
LeeS KimC ShinH KhoY ChoiK Comparison of thyroid hormone disruption potentials by bisphenols A, S, F, and Z in embryo-larval zebrafish. Chemosphere2019221115123DOI: 10.1016/j.chemosphere.2019.01.019 PMid:30639807
[15]
KimMJ ParkYJ Bisphenols and Thyroid Hormone. Endocrinol Metab (Seoul, Korea)201934340348DOI: 10.3803/EnM.2019.34.4.340 PMid:31884733 PMCid:PMC6935774
[16]
RezgR El-FazaaS GharbiN MornaguiB Bisphenol A and human chronic diseases: current evidences, possible mechanisms, and future perspectives. Environ Int2014648390DOI: 10.1016/j.envint.2013.12.007 PMid:24382480
[17]
SeachristDD BonkKW HoSM PrinsGS SotoAM KeriRA A review of the carcinogenic potential of bisphenol A, http://www.ncbi.nlm.nih.gov/pubmed/26493093,2016DOI: 10.1016/j.reprotox.2015.09.006 PMid:26493093 PMCid:PMC4783235
[18]
CampesiI MarinoM MontellaA PaisS FranconiF Sex Differences in Estrogen Receptor α and β Levels and Activation Status in LPS-Stimulated Human Macrophages,2017DOI: 10.1002/jcp.25425 PMid:27171902
[19]
WangY WangL ZhaoJ QiaoZ Estrogen, but not testosterone, down-regulates cytokine production in nicotine-induced murine macrophage. Methods Find Exp Clin Pharmacol200527311316DOI: 10.1358/mf.2005.27.5.893666 PMid:16082418
[20]
HongC-C Shimomura-ShimizuM MuroiM TanamotoK Effect of endocrine disrupting chemicals on lipopolysaccharide-induced tumor necrosis factor-alpha and nitric oxide production by mouse macrophages. Biol Pharm Bull20042711361139DOI: 10.1248/bpb.27.1136 PMid:15256756
[21]
YamashitaU SugiuraT YoshidaY KurodaE Effect of endocrine disrupters on macrophage functionsin vitro. J UOEH200527110DOI: 10.7888/juoeh.27.1_1 PMid:15794588
[22]
LuX LiM WuC ZhouC ZhangJ ZhuQ ShenT Bisphenol A promotes macrophage proinflammatory subtype polarization via upregulation of IRF5 expression in vitro. ToxicolIn vitro20196097106DOI: 10.1016/j.tiv.2019.05.013 PMid:31108126
[23]
KuanYH HuangFM LiYC ChangYC Proinflammatory activation of macrophages by bisphenol A-glycidyl-methacrylate involved NF??B activation via PI3K/Akt pathway. Food Chem Toxicol20125040034009DOI: 10.1016/j.fct.2012.08.019 PMid:22939937
[24]
LiuY MeiC LiuH WangH ZengG LinJ XuM Modulation of cytokine expression in human macrophages by endocrine-disrupting chemical Bisphenol-A. Biochem Biophys Res Commun2014451592598DOI: 10.1016/j.bbrc.2014.08.031 PMid:25128825
[25]
TeixeiraD MarquesC PestanaD FariaA NorbertoS CalhauC MonteiroR Effects of xenoestrogens in human M1 and M2 macrophage migration, cytokine release, and estrogen-related signaling pathways. Environ Toxicol20163114961509DOI: 10.1002/tox.22154 PMid:26011183
[26]
YangM QiuW ChenB ChenJ LiuS WuM WangKJ Thein vitro immune modulatory effect of bisphenol a on fish macrophages via estrogen receptor ?? and Nuclear Factor-??B signaling. Environ Sci Technol20154918881895DOI: 10.1021/es505163v PMid:25565130
[27]
SeguraJJ Jiménez-RubioA PulgarR OleaN GuerreroJM CalvoJR In vitro Effect of the Resin Component Bisphenol A on Substrate Adherence Capacity of Macrophages. J Endod199925341344DOI: 10.1016/S0099-2399(06)81168-4
[28]
KimJ Young JeongH Gwang Down-regulation of inducible nitric oxide synthase and tumor necrosis factor-α expression by bisphenol A via nuclear factor-κB inactivation in macrophages. Cancer Lett20031966976DOI: 10.1016/S0304-3835(03)00219-2
[29]
ByunJA HeoY KimYO PyoMY Bisphenol A-induced downregulation of murine macrophage activitiesin vitro and ex vivo. Environ Toxicol Pharmacol2005191924DOI: 10.1016/j.etap.2004.02.006 PMid:21783458
[30]
OhnishiT YoshidaT IgarashiA MuroiM TanamotoKI Effects of possible endocrine disruptors on MyD88-independent TLR4 signaling. FEMS Immunol Med Microbiol200852293295DOI: 10.1111/j.1574-695X.2007.00355.x PMid:18177342
[31]
YoshitakeJ KatoK YoshiokaD SueishiY SawaT AkaikeT YoshimuraT Suppression of NO production and 8-nitroguanosine formation by phenol-containing endocrine-disrupting chemicals in LPS-stimulated macrophages: involvement of estrogen receptor-dependent or -independent pathways. Nitric oxide Biol Chem2008182238DOI: 10.1016/j.niox.2008.01.003 PMid:18252206
[32]
KimKH YeonSM KimHG ChoiHS KangH ParkHD ParkTW PackSP LeeEH ByunY ChoiSE LeeKS HaUH JungYW Diverse influences of androgen-disrupting chemicals on immune responses mounted by macrophages. Inflammation201437649656DOI: 10.1007/s10753-013-9781-1 PMid:24287822
[33]
LiuS PanC TangY ChenF YangM WangKJ Identification of novel long non-coding RNAs involved in bisphenol A induced immunotoxicity in fish primary macrophages. Fish Shellfish Immunol2020100152160DOI: 10.1016/j.fsi.2020.03.006 PMid:32147374
[34]
KovatsS Estrogen receptors regulate innate immune cells and signaling pathways. Cell Immunol20152946369DOI: 10.1016/j.cellimm.2015.01.018 PMid:25682174 PMCid:PMC4380804
[35]
GuoH LiuT UemuraY JiaoS WangD LinZ NaritaY SuzukiM HirosawaN IchiharaY IshiharaO KikuchiH SakamotoY SenjuS ZhangQ LingF Bisphenol A in combination with TNF-alpha selectively induces Th2 cell-promoting dendritic cellsin vitro with an estrogen-like activity. Cell Mol Immunol2010722734DOI: 10.1038/cmi.2010.14 PMid:20383177 PMCid:PMC4002911
[36]
PisapiaL PozzoG Del BarbaP CaputoL MitaL ViggianoE RussoGL NicolucciC RossiS BencivengaU MitaDG DianoN Effects of some endocrine disruptors on cell cycle progression and murine dendritic cell differentiation. Gen Comp Endocrinol20121785463DOI: 10.1016/j.ygcen.2012.04.005 PMid:22531466
[37]
ŠvajgerU DolencMS JerasM impact of bisphenols BPA, BPF, BPAF and 17β-estradiol (E2) on human monocyte-derived dendritic cell generation, maturation and function. Int ImmunopharmacolIn vitro201634146154DOI: 10.1016/j.intimp.2016.02.030 PMid:26945833
[38]
CamarcaA GianfraniC AriemmaF CimminoI BruzzeseD ScerboR PicasciaS D'EspositoV BeguinotF FormisanoP ValentinoRV Human peripheral blood mononuclear cell function and dendritic cell differentiation are affected by bisphenol-A exposure. PLoS One201611118DOI: 10.1371/journal.pone.0161122 PMid:27509021 PMCid:PMC4980038
[39]
ChakhtouraM SriramU HeaynM WonsidlerJ DoyleC DinnallJ-A GallucciS RobertsRA Bisphenol A Does Not Mimic Estrogen in the Promotion of theIn vitro Response of Murine Dendritic Cells to Toll-Like Receptor Ligands. Mediators Inflamm201720172034348DOI: 10.1155/2017/2034348 PMid:28811679 PMCid:PMC5547709
[40]
WatanabeH AdachiR KusuiK HirayamaA KasaharaT SuzukiK Bisphenol A significantly enhances the neutrophilic differentiation of promyelocytic HL-60 cells. Int Immunopharmacol2003316011608DOI: 10.1016/S1567-5769(03)00182-6
[41]
ReistadT MariussenE FonnumF The effect of a brominated flame retardant, tetrabromobisphenol-A, on free radical formation in human neutrophil granulocytes: The involvement of the MAP kinase pathway and protein kinase C. Toxicol Sci20058389100DOI: 10.1093/toxsci/kfh298 PMid:15456914
[42]
Midoro-HoriutiT TiwariR WatsonCS GoldblumRM Maternal bisphenol a exposure promotes the development of experimental asthma in mouse pups. Environ Health Perspect2010118273277DOI: 10.1289/ehp.0901259 PMid:20123615 PMCid:PMC2831929
[43]
HeM IchinoseT YoshidaS TakanoH NishikawaM ShibamotoT SunG Exposure to bisphenol A enhanced lung eosinophilia in adult male mice. Allergy Asthma Clin Immunol20161216DOI: 10.1186/s13223-016-0122-4 PMid:27087817 PMCid:PMC4832452
[44]
MénardS Guzylack-PiriouL LencinaC LevequeM NaturelM SekkalS HarkatC GaultierE OlierM Garcia-VillarR TheodorouV HoudeauE Perinatal exposure to a low dose of bisphenol a impaired systemic cellular immune response and predisposes young rats to intestinal parasitic infection. PLoS One20149115DOI: 10.1371/journal.pone.0112752 PMid:25415191 PMCid:PMC4240706
[45]
O'BrienE DolinoyDC MancusoP Bisphenol A at concentrations relevant to human exposure enhances histamine and cysteinyl leukotriene release from bone marrow-derived mast cells. J Immunotoxicol201411849DOI: 10.3109/1547691X.2013.800925 PMid:23782309 PMCid:PMC4030600
[46]
O'BrienE DolinoyDC MancusoP Perinatal bisphenol A exposures increase production of pro-inflammatory mediators in bone marrow-derived mast cells of adult mice. J Immunotoxicol201411205212DOI: 10.3109/1547691X.2013.822036 PMid:23914806 PMCid:PMC3983174
[47]
KleinSL FlanaganKL Sex differences in immune responses. Nat Rev Immunol advance on2016DOI: 10.1038/nri.2016.90 PMid:27546235
[48]
Ahmed S Ansar Penhale WJ Talal N Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action. Am J Pathol 1985 121 531 51
[49]
Salem M Labib Hossain M Sohrab Nomoto K Mediation of the Immunomodulatory Effect of ß-Estradiol on Inflammatory Responses by Inhibition of Recruitment and Activation of Inflammatory Cells and Their Gene Expression of TNF-· and IFN-Á. Int Arch Allergy Immunol 2000 121121
[50]
YounJ-Y ParkH-Y LeeJ-W JungI-O ChoiK-H KimK ChoK-H Evaluation of the immune response following exposure of mice to bisphenol A: induction of Th1 cytokine and prolactin by BPA exposure in the mouse spleen cells. Arch Pharm Res20022594653DOI: 10.1007/BF02977018 PMid:12510852
[51]
YoshinoS YamakiK YanagisawaR TakanoH HayashiH MoriY Effects of bisphenol A on antigen-specific antibody production, proliferative responses of lymphoid cells, and TH1 and TH2 immune responses in mice. Br J Pharmacol200313812716DOI: 10.1038/sj.bjp.0705166 PMid:12711627 PMCid:PMC1573776
[52]
YoshinoS YamakiK LiX SaiTAO TakanoH HayashiH Prenatal exposure to bisphenol A up-regulates immune responses , including T helper 1 and T helper 2 responses , in mice. Immunology2004112495DOI: 10.1111/j.1365-2567.2004.01900.x PMid:15196218 PMCid:PMC1782504
[53]
AlizadehM OtaF HosoiK KatoM SakaiT SatterM Altered allergic cytokine and antibody response inmice treated with Bisphenol A. J Med Invest2006537080DOI: 10.2152/jmi.53.70 PMid:16537998
[54]
MénardS Guzylack-PiriouL LevequeM BranisteV LencinaC NaturelM MoussaL SekkalS HarkatC GaultierE TheodorouV HoudeauE Food intolerance at adulthood after perinatal exposure to the endocrine disruptor bisphenol A. FASEB J20142848934900DOI: 10.1096/fj.14-255380 PMid:25085925
[55]
HolladaySD XiaoS DiaoH BarberJ NagyT YeX GogalRM Perinatal bisphenol a exposure in C57B6/129svj male mice: Potential altered cytokine/chemokine production in adulthood. Int J Environ Res Public Health2010728452852DOI: 10.3390/ijerph7072845 PMid:20717544 PMCid:PMC2922731
[56]
LuoS LiY LiY ZhuQ JiangJ WuC ShenT Gestational and lactational exposure to low-dose bisphenol A increases Th17 cells in mice offspring. Environ Toxicol Pharmacol201647149158DOI: 10.1016/j.etap.2016.09.017 PMid:27693988
[57]
LeeJ LimK-T Plant-originated glycoprotein (36 kDa) suppresses interleukin-4 and -10 in bisphenol A-stimulated primary cultured mouse lymphocytes. Drug Chem Toxicol2010334219DOI: 10.3109/01480541003739229 PMid:20553123
[58]
LeeMH ChungSW KangBY ParkJ LeeCH HwangSY KimTS Enhanced interleukin-4 production in CD4+ T cells and elevated immunoglobulin E levels in antigen-primed mice by bisphenol A and nonylphenol, endocrine disruptors: Involvement of nuclear factor-AT and CA2+. Immunology20031097686DOI: 10.1046/j.1365-2567.2003.01631.x PMid:12709020 PMCid:PMC1782943
[59]
MiaoS GaoZ KouZ XuG SuC LiuN Influence of bisphenol a on developing rat estrogen receptors and some cytokines in rats: a two-generational study. J Toxicol Environ Health A20087110001008DOI: 10.1080/15287390801907467 PMid:18569609
[60]
SawaiC AndersonK Walser-KuntzD Effect of bisphenol A on murine immune function: Modulation of interferon-gamma, IgG2a, and disease symptoms in NZB X NZW F1 mice. Environ Health Perspect200311118831887DOI: 10.1289/ehp.6359 PMid:14644661 PMCid:PMC1241761
[61]
OhshimaY YamadaA TokurikiS YasutomiM OmataN MayumiM Transmaternal exposure to bisphenol a modulates the development of oral tolerance. Pediatr Res2007626064DOI: 10.1203/PDR.0b013e3180674dae PMid:17515845
[62]
YurinoH IshikawaS SatoT AkadegawaK ItoT UehaS InaderaH MatsushimaK Endocrine disruptors (environmental estrogens) enhance autoantibody production by B1 cells. Toxicol Sci200481139147DOI: 10.1093/toxsci/kfh179 PMid:15166399
[63]
GotoM Takano-IshikawaY OnoH YoshidaM YamakiK ShinmotoH Orally administered bisphenol A disturbed antigen specific immunoresponses in the naïve condition. Biosci Biotechnol Biochem200771213643DOI: 10.1271/bbb.70004 PMid:17827700
[64]
RoyA BauerSM LawrenceBP Developmental exposure to bisphenol a modulates innate but not adaptive immune responses to influenza a virus infection. PLoS One20127112DOI: 10.1371/journal.pone.0038448 PMid:22675563 PMCid:PMC3366985
[65]
Sugita-KonishiY ShimuraS NishikawaT SunagaF NaitoH SuzukiY Effect of Bisphenol A on non-specific immunodefenses against non-pathogenic Escherichia coli. Toxicol Lett2003136217227DOI: 10.1016/S0378-4274(02)00388-0
[66]
LaiK-P ChungY-T LiR WanH-T WongCK-C Bisphenol A alters gut microbiome: Comparative metagenomics analysis. Environ Pollut2016218923930DOI: 10.1016/j.envpol.2016.08.039 PMid:27554980
[67]
JavurekAB SpollenWG JohnsonSA BivensNJ BromertKH GivanSA RosenfeldCS Effects of exposure to bisphenol A and ethinyl estradiol on the gut microbiota of parents and their offspring in a rodent model. Gut Microbes20167471485DOI: 10.1080/19490976.2016.1234657 PMid:27624382 PMCid:PMC5103659
[68]
YanH TakamotoM SuganeK Exposure to bisphenol A prenatally or in adulthood promotes TH2 cytokine production associated with reduction of CD4+CD25+ regulatory T cells. Environ Health Perspect2008116514519DOI: 10.1289/ehp.10829 PMid:18414636 PMCid:PMC2290985
[69]
TianX TakamotoM SuganeK Bisphenol A promotes IL-4 production by Th2 cells. Int Arch Allergy Immunol2003132240247DOI: 10.1159/000074305 PMid:14646385
[70]
Nava-CastroKE Solleiro-VillavicencioH Río-AraizaVH del Segovia-MendozaM Pérez-TorresA Morales-MontorJ Sex-associated protective effect of early bisphenol-A exposure during enteric infection with Trichinella spiralis in mice. PLoS One201914114DOI: 10.1371/journal.pone.0218198 PMid:31291264 PMCid:PMC6619665
[71]
Nava-Castro KE Togno-Peirce C Palacios-Arreola MI Río-Araiza VH Del Segovia-Mendoza M Hernández-Bello R Montor J Morales Exposure to the endocrine disruptor compound Bisphenol A induces protection through modulation of the immune response against the helminth parasite Taenia crassiceps. Par Immunol. In press
[72]
Río-AraizaVH Del Palacios-ArreolaMI Nava-CastroKE Pérez-SánchezNY Ruíz-ManzanoR Segovia-MendozaM Girón-PérezMI Navidad-MurrietaMS Morales-MontorJ Perinatal exposure to bisphenol A increases in the adulthood of the offspring the susceptibility to the human parasite Toxocara canis. Environ Res2020184110DOI: 10.1016/j.envres.2020.109381 PMid:32199324
[73]
TanL WangS WangY HeM LiuD Bisphenol A exposure accelerated the aging process in the nematode Caenorhabditis elegans. Toxicol Lett20152357583DOI: 10.1016/j.toxlet.2015.03.010 PMid:25819108
[74]
MershaMD PatelBM PatelD RichardsonBN DhillonHS Effects of BPA and BPS exposure limited to early embryogenesis persist to impair non-associative learning in adults. Behav Brain Funct20151127DOI: 10.1186/s12993-015-0071-y PMid:26376977 PMCid:PMC4573949
[75]
ZhouD YangJ LiH LuQ LiuY Di LinKF Ecotoxicity of bisphenol A to Caenorhabditis elegans by multigenerational exposure and variations of stress responsein vivo across generations. Environ Pollut2016208767773DOI: 10.1016/j.envpol.2015.10.057 PMid:26561446
[76]
ZhouD YangJ LiH CuiC YuY LiuY LinK The chronic toxicity of bisphenol A to Caenorhabditis elegans after long-term exposure at environmentally relevant concentrations. Chemosphere2016154546551DOI: 10.1016/j.chemosphere.2016.04.011 PMid:27085314
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