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Wednesday, July 1, 2009

Food Hypersensitivity & Bisphenol A

Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
June 30, 2009

In 2007, Ohshima and colleagues reported that levels of a plastics chemical known as bisphenol A (BPA) were inversely correlated with oral tolerance which - when suboptimal - is associated with food hypersensitivities and autoimmunity (1).

Background: Allergies to various foods are increasing in the U.S. and elsewhere (2). More than 60% among >2500 autism parents reported improvements when their autistic child is on a gluten-free or casein-free diet (3). Bisphenol A has become common in breast milk, cord blood, and bodies of humans (eg, 4-8) and may be etiologically significant in some and perhaps many cases of food hypersensitivity (1). As cited below, other BPA effects may be relevant to autism.

First, a technical but important aside: BPA was found to alter function of immune cells labeled with surface markers known as CD4 and CD25 (1). These cells participate in immunological anergy and, when functioning properly, minimize or prevent autoimmunity and induce appropriate oral tolerance to food antigens (1, 9-11).

Caveat and counter-caveat: The Ohshima et al findings occurred in a murine model wherein BPA levels were substantially higher than average levels found in humans (1). However, the findings may pertain to humans with impaired detoxification. For instance, glutathione participates in neutralization and detoxification of BPA (eg, 12-13). Many humans have one or more polymorphisms which diminish effectiveness or availability of glutathione (eg, 14-15). And weak alleles in GSH-related pathways are increasingly described in autism (eg, 16-17). Furthermore, BPA detoxification includes glucuronidation, which can be affected by polymorphisms (eg, 18) and BPA-detoxification is affected by androgens (19-21). Lower levels of GSH, suboptimal utilization of GSH, weak alleles of genes participating in glucuronidation, and elevated androgens are factors suggesting relevance of BPA's role in food hypersensitivities among infants and children with impaired ability to detoxify BPA.

As prompted by the BPA oral-tolerance findings of Ohshima et al (1), a preliminary survey of peer-reviewed literature led to other parallels possibly relevant to BPA in children who become autistic or have one of the other autism-spectrum disorders.

1a. BPA levels are increased in the presence of androgens (19-21).
1b. Autism subgroups with polymorphisms in detox genes have been described (16-17).
1c. Research has identified autism subgroups with elevated androgens (22-23).

2a. BPA may affect natural killer (NK) cell function via BPA's effects upon CD4 CD25 T-regulatory (Treg cells) (24, 1).
2b. Researches have identified autism subgroups with low NK-cytotoxicity (25-26)

3a. BPA may alter expression of Toll-like receptors (TLRs) via BPA's effects upon CD4 CD25 Treg cells (27, 1).
3b. Atypical TLR reponses have been described in a subgroup of autism-spectrum children (28).

Conclusion: BPA may be relevant in various ways for subgroups of children with autism or other autism-spectrum disorders. Two pathways by which BPA is detoxified can be affected by genetic polymorphisms. That androgens modulate BPA levels suggests that boys are more likely to be affected, but clinical data are showing that, aside from autistic males, some females with autism have elevated androgens and thus may have atypically elevated levels of BPA. Furthermore, numerous pollutants - not just BPA - have found their way into human bodies and would contribute to utilization and possible depletion of nutrients needed for detoxification. In this complex context, BPA may contribute to food hypersensitivities in some children.


1: Transmaternal exposure to bisphenol a modulates the development of oral tolerance.
Ohshima Y et al. Pediatr Res. 2007 62(1):60-4.

Bisphenol A (BPA) is a representative endocrine disruptor that may have adverse effects on human health. Since the development of oral tolerance during infancy may play an important role in the prevention of food allergies, we examined whether transmaternal exposure to BPA influences the development of oral tolerance. To measure antigen-specific responses, female wild-type mice mated with male ovalbumin (OVA)-specific T-cell receptor transgenic (TCR-tg) mice were fed with BPA during pregnancy and while nursing. OVA was administered to OVA-TCR-tg offspring during their weaning period. Oral administration of both high and low doses of OVA suppressed OVA-specific cell proliferation and cytokine production in both BPA-exposed and nonexposed control mice, but the OVA-mediated suppression was significantly more diminished by the BPA exposure. The accumulation of CD4+CD25+Foxp3+ T cells was diminished in the BPA-exposed offspring. Moreover, after low dose OVA administration, serum OVA-specific IgG1 and IgG2a levels were higher in the BPA-exposed offspring than in nonexposed ones. Taken together, our results indicate that transmaternal exposure to BPA seems to modulate the mechanisms underlying tolerance induction; therefore, BPA may partially interrupt the development of oral tolerance.

2: Update on food allergy.
Sampson HA. J Allergy Clin Immunol. 2004 113(5):805-19.

3. Parent Ratings of Behavorial Effects of Biomedical Interventions
Autism Research Institute

4. Parent bisphenol A accumulation in the human maternal-fetal-placental unit.
Schönfelder G et al. Environ Health Perspect. 2002 110(11):A703-7.
{free online}

Bisphenol A (BPA), an endocrine disruptor, is employed in the manufacture of a wide range of consumer products. The suggestion that BPA, at amounts to which we are exposed, alters the reproductive organs of developing rodents has caused concern. At present, no information exists concerning the exposure of human pregnant women and their fetuses to BPA. We therefore investigated blood samples from mothers (n = 37) between weeks 32 and 41 of gestation. Afer the births, we also analyzed placental tissue and umbilical cord blood from the same subjects. We developed a novel chemical derivatization-gas chromatography/mass spectrometry method to analyze parent BPA at concentrations < median =" 3.1" median =" 2.3" median =" 12.7" r =" 0.994)" artid="2610366&blobtype="> A), transcobalamin II (TCN2 776G > C), catechol-O-methyltransferase (COMT 472G > A), methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C), and glutathione-S-transferase (GST M1). We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and clinical manifestations of autism.

17. Risk of autistic disorder in affected offspring of mothers with a glutathione S-transferase P1 haplotype.
Williams TA et al. Arch Pediatr Adolesc Med. 2007 161(4):356-61.
{free online}

OBJECTIVE: To test whether polymorphisms of the glutathione S-transferase P1 gene (GSTP1) act in the mother during pregnancy to contribute to the phenotype of autistic disorder (AD) in her fetus. DESIGN: Transmission disequilibrium testing (TDT) in case mothers and maternal grandparents. SETTING: Autistic disorder may result from multiple genes and environmental factors acting during pregnancy and afterward. Teratogenic alleles act in mothers during pregnancy to contribute to neurodevelopmental disorders in their offspring; however, only a handful have been identified. GSTP1 is a candidate susceptibility gene for AD because of its tissue distribution and its role in oxidative stress, xenobiotic metabolism, and JNK regulation. PARTICIPANTS: We genotyped GSTP1*G313A and GSTP1*C341T polymorphisms in 137 members of 49 families with AD. All probands received a clinical diagnosis of AD by Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule-Generic testing. MAIN OUTCOME MEASURES: Association of haplotypes with AD was tested by the TDT-Phase program, using the expectation-maximization (EM) algorithm for uncertain haplotypes and for incomplete parental genotypes, with standard measures of statistical significance. RESULTS: The GSTP1*A haplotype was overtransmitted to case mothers (P = .01 [P = .03 using permutation testing]; odds ratio, 2.67 [95% confidence interval, 1.39-5.13]). Results of the combined haplotype and genotype analyses suggest that the GSTP1-313 genotype alone determined the observed haplotype effect. CONCLUSIONS: Overtransmission of the GSTP1*A haplotype to case mothers suggests that action in the mother during pregnancy likely increases the likelihood of AD in her fetus. If this is confirmed and is a result of a gene-environment interaction occurring during pregnancy, these findings could lead to the design of strategies for prevention or treatment.

18. Elevated serum bisphenol A levels under hyperandrogenic conditions may be caused by decreased UDP-glucuronosyltransferase activity.
Takeuchi T et al. Endocr J. 2006 Aug;53(4):485-91. Epub 2006 Jul 10.

This study was performed to investigate the effect of androgen on the metabolism of bisphenol A (BPA), an endocrine disruptor, in order to clarify the mechanism of the higher levels of serum BPA in men and hyperandrogenemic women compared with normal women. Castrated female rats (OVX) were subcutaneously injected with testosterone propionate (TP) (0.01, 0.1, and 1 mg) every day for 2 weeks. Serum BPA concentrations in OVX rats showed a TP dose-dependent increase and were significantly higher at 0.1 and 1.0 mg of TP. The enzyme reaction of BPA glucuronidation in the rat liver microsomes showed that the ratio of glucuronide in the OVX rats was significantly reduced in a TP dose-dependent manner. Analysis of the mRNA expression of UDP-glucuronosyltransferase 2B1 (UGT2B1) by real-time quantitative RT-PCR revealed that the relative expression level of UGT2B1 mRNA showed a TP dose-dependent decrease. The results of enzyme analyses demonstrated that the ratio of BPA glucuronidation and the expression level of UGT2B1 mRNA were significantly lower under the hyperandrogenemic conditions. The clearance of BPA may be slowed in a TP dose-dependent manner, resulting in an increase of serum BPA concentration under hyperandrogenemic conditions.

19. Positive relationship between androgen and the endocrine disruptor, bisphenol A, in normal women and women with ovarian dysfunction.
Takeuchi T et al. Endocr J. 2004 Apr;51(2):165-9.
{free online}

This study was performed to investigate the serum levels of bisphenol A (BPA), an endocrine disruptor, in women with ovarian dysfunction and obesity. Fasting serum samples were obtained from 19 non-obese and 7 obese women with normal menstrual cycles: 7 patients with hyperprolactinemia, 21 patients with hypothalamic amenorrhea, and 13 non-obese and 6 obese patients with polycystic ovary syndrome (PCOS). BPA was measured by an enzyme-linked immunosorbent assay. BPA was detected in all human sera. Serum BPA concentrations were significantly higher in both non-obese and obese women with polycystic ovary syndrome (1.05 +/- 0.10 ng/ml, 1.17 +/- 0.16 ng/ml; p<0.05, r =" 0.391," r =" 0.504," r =" 0.684," r =" 0.514," r =" 0.595," r =" 0.609," r =" 0.559," r =" 0.598,">

23. Spironolactone might be a desirable immunologic and hormonal intervention in autism spectrum disorders.
Bradstreet JJ et al. Med Hypotheses. 2007;68(5):979-87. Epub 2006 Dec 5.

Multiple studies now demonstrate that autism is medically characterized, in part, by immune system dysregulation, including evidence of neuroglial activation and gastrointestinal inflammation. This neuroglial process has further been characterized as neuroinflammation. In addition, a subset of autistic children exhibit higher than average levels of androgens. Spironolactone is an aldosterone antagonist and potassium-sparing diuretic with a desirable safety profile. It possesses potent anti-inflammatory and immune modifying properties that might make it an excellent medical intervention for autism spectrum disorders. Furthermore, spironolactone demonstrates substantial anti-androgen properties that might further enhance its appeal in autism, particularly in a definable subset of hyperandrogenic autistic children. One case report is briefly reviewed demonstrating objective clinical improvements in an autistic child after spironolactone administration. Additional research in controlled trials is now needed to further define the risks and benefits of spironolactone use in children with autism.

24. Control of NK cell functions by CD4+CD25+ regulatory T cells.
Ralainirina N et al. J Leukoc Biol. 2007 Jan;81(1):144-53.
{free online}

Regulatory T cells (Treg) are key players in the maintenance of peripheral tolerance. As a result of suppressive effects on CD4+ and CD8+ effector T cells, Treg control the adaptive immune system and prevent autoimmunity. In addition, they inhibit B lymphocytes, dendritic cells, and monocytes/macrophages. It is interesting that several recent papers show that CD4+CD25+ Treg are also able to inhibit NK cells. Thus, Treg exert their control on immune responses from the onset (triggering of innate immune cells) to the effector phase of adaptive immunity (B and T cell-mediated responses). That Treg inhibit NK cells suggests that their uncontrolled activation might break self-tolerance and induce "innate" autoimmune pathology. Conversely, Treg-mediated suppression of NK cell functions might have negative effects, as these cells are important in defense against infections and cancer. It is conceivable that Treg might dampen efficient activation of NK cells in these diseases.

25. Reduced natural killer cell activity in autism.
Warren RP et al. J Am Acad Child Adolesc Psychiatry. 1987 26(3):333-5.

26. Low natural killer cell cytotoxic activity in autism: the role of glutathione, IL-2 and IL-15.
Vojdani A et al. J Neuroimmunol. 2008 Dec 15;205(1-2):148-54.

Although many articles have reported immune abnormalities in autism, NK cell activity has only been examined in one study of 31 patients, of whom 12 were found to have reduced NK activity. The mechanism behind this low NK cell activity was not explored. For this reason, we explored the measurement of NK cell activity in 1027 blood samples from autistic children obtained from ten clinics and compared the results to 113 healthy controls. This counting of NK cells and the measurement of their lytic activity enabled us to express the NK cell activity/100 cells. At the cutoff of 15-50 LU we found that NK cell activity was low in 41-81% of the patients from the different clinics. This NK cell activity below 15 LU was found in only 8% of healthy subjects (p<0.001). Low NK cell activity in both groups did not correlate with percentage and absolute number of CD16(+)/CD56(+) cells. When the NK cytotoxic activity was expressed based on activity/100 CD16(+)/CD56(+) cells, several patients who had displayed NK cell activity below 15 LU exhibited normal NK cell activity. Overall, after this correction factor, 45% of the children with autism still exhibited low NK cell activity, correlating with the intracellular level of glutathione. Finally, we cultured lymphocytes of patients with low or high NK cell activity/cell with or without glutathione, IL-2 and IL-15. The induction of NK cell activity by IL-2, IL-15 and glutathione was more pronounced in a subgroup with very low NK cell activity. We conclude that that 45% of a subgroup of children with autism suffers from low NK cell activity, and that low intracellular levels of glutathione, IL-2 and IL-15 may be responsible.

27. Toll-like receptors and immune regulation: their direct and indirect modulation on regulatory CD4+ CD25+ T cells.
Liu G, Zhao Y. Immunology. 2007 122(2):149-56.
{free online}

28. Impact of innate immunity in a subset of children with autism spectrum disorders: a case control study.
Jyonouchi H et al. J Neuroinflammation. 2008 Nov 21;5:52.
{free online}

BACKGROUND: Among patients with autism spectrum disorders (ASD) evaluated in our clinic, there appears to be a subset that can be clinically distinguished from other ASD children because of frequent infections (usually viral) accompanied by worsening behavioural symptoms and/or loss/decrease in acquired skills. This study assessed whether these clinical features of this ASD subset are associated with atopy, asthma, food allergy (FA), primary immunodeficiency (PID), or innate immune responses important in viral infections. METHODS: This study included the ASD children described above (ASD test, N = 26) and the following controls: ASD controls (N = 107), non-ASD controls with FA (N = 24), non-ASD controls with chronic rhinosinusitis/recurrent otitis media (CRS/ROM; N = 38), and normal controls (N = 43). We assessed prevalence of atopy, asthma, FA, CRS/ROM, and PID. Innate immune responses were assessed by measuring production of proinflammatory and counter-regulatory cytokines by peripheral blood mononuclear cells (PBMCs) in response to agonists of Toll-like receptors (TLRs), with or without pre-treatment of lipopolysaccharide (LPS), a TLR4 agonist. RESULTS: Non-IgE mediated FA was equally prevalent in both ASD test and ASD control groups, occurring at higher frequency than in the non-ASD controls. Allergic rhinitis, atopic/non-atopic asthma, and atopic dermatitis were equally prevalent among the study groups except for the CRS/ROM group in which non-atopic asthma was more prevalent (52.6%). CRS/ROM and specific polysaccharide antibody deficiency (SPAD) were more prevalent in the ASD test group than in the ASD control, FA, and normal control groups: 23.1% vs. < 5% for CRS/ROS and 19.2% vs. < 1% for SPAD. However, CRS/ROM patients had the highest prevalence of SPAD (34.2%). When compared to ASD and normal case controls, PBMCs from 19 non-SPAD, ASD test group children produced: 1) less IL-1beta with a TLR7/8 agonist, less IL-10 with a TLR2/6 agonist, and more IL-23 with a TLR4 agonist without LPS pre-treatment, and 2) less IL-1beta with TLR4/7/8 agonists with LPS pre-treatment. These are cytokines associated with the neuro-immune network. CONCLUSION: Clinical features of the ASD test group were not associated with atopy, asthma, FA, or PID in our study but may be associated with altered TLR responses mediating neuro-immune interactions.

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