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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.
References:
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
http://www.autism.com/treatable/form34qr.htm
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} http://tinyurl.com/l34o5l
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 < 1 micro g/mL in plasma and tissues. Concentrations
of BPA ranged from 0.3 to 18.9 ng/mL (median = 3.1 ng/mL) in maternal
plasma, from 0.2 to 9.2 ng/mL (median = 2.3 ng/mL) in fetal plasma, and
from 1.0 to 104.9 ng/g (median = 12.7 ng/g) in placental tissue. BPA
blood concentrations were higher in male than in female fetuses. Here
we demonstrate parent BPA in pregnant women and their fetuses. Exposure
levels of parent BPA were found within a range typical of those used in
recent animal studies and were shown to be toxic to reproductive organs
of male and female offspring. We suggest that the range of BPA
concentrations we measured may be related to sex differences in
metabolization of parent BPA or variable maternal use of consumer
products leaching BPA.
5. Determination of bisphenol A concentrations in human biological fluids reveals significant early prenatal exposure.
Ikezuki Y et al. Hum Reprod. 2002 17(11):2839-41.
{free online} http://humrep.oxfordjournals.org/cgi/content/full/17/11/2839
BACKGROUND: There is broad human exposure to bisphenol A (BPA), an
estrogenic endocrine-disrupting chemical widely used for the production
of plastic products. BPA is reported to affect preimplantation embryos
or fetuses and alter their postnatal development at doses typically
found in the environment. We measured contamination of BPA in various
kinds of human biological fluids by a novel enzyme-linked immunosorbent
assay. METHODS: Blood samples were obtained from healthy premenopausal
women, women with early and full-term pregnancy, and umbilical cord at
full-term delivery. Ovarian follicular fluids obtained during IVF
procedures and amniotic fluids obtained at mid-term and full-term
pregnancy were also subject to BPA measurements. RESULTS: BPA was
present in serum and follicular fluid at approximately 1-2 ng/ml, as
well as in fetal serum and full-term amniotic fluid, confirming passage
through the placenta. Surprisingly, an approximately 5-fold higher
concentration, 8.3 +/- 8.7 ng/ml, was revealed in amniotic fluid at
15-18 weeks gestation, compared with other fluids. CONCLUSION: These
results suggest accumulation of BPA in early fetuses and significant
exposure during the prenatal period, which must be considered in
evaluating the potential for human exposure to endocrine-disrupting
chemicals.
6. Determination of bisphenol A in human breast milk by HPLC with column-switching and fluorescence detection.
Sun Y et al. Biomed Chromatogr. 2004 18(8):501-7.
A highly sensitive HPLC method was developed for the determination of
xenoestrogenic compound, bisphenol A (BPA) in human breast milk
samples. After a two-step liquid-liquid extraction, BPA was derivatized
with fluorescent labeling reagent,
4-(4,5-diphenyl-1H-imidazol-2-yl)benzoyl chloride (DIB-Cl). The excess
fluorescent reagent could be removed effectively using a
column-switching system. The separation of DIB-BPA from endogenous
materials in milk was carried out on two C(18) columns and fluorescence
intensity was monitored at 475 nm with the excitation of 350 nm. A good
linearity (r = 0.994) was observed of BPA in the concentration range of
0.2-5.0 ng mL(-1) in breast milk, and the detection limit was 0.11 ng
mL(-1) at a signal-to-noise ratio of 3. Intra- and inter-day precision
(RSD, %) were less than 8.7 and 10.4, respectively. Twenty-three breast
milk samples of healthy lactating women were analyzed for the BPA
concentration; the mean value was 0.61 +/- 0.20 ng mL(-1), with no
correlation to the lipid content of milk samples.
7. Measurement of bisphenol A concentrations in human colostrum.
Kuruto-Niwa R et al. Chemosphere. 2007 Jan;66(6):1160-4.
Bisphenol A (BPA), an estrogenic endocrine disrupting chemical, has
been reported to affect embryos and alter their postnatal development.
In the present study, we measured the concentrations of BPA in human
colostrum by a competitive enzyme-linked immunosorbent assay (ELISA)
with the aim of understanding the present status of BPA burden in human
breast milk in Shizuoka, Japan. Human colostral samples were collected
from 101 healthy mothers within three days after delivery. The BPA
concentrations of colostral samples were estimated by ELISA after the
acetonitrile extraction and solid phase extraction column purification.
BPA in 101 samples was detected in the concentration range of 1-7 ng
ml(-1). The mean concentration of BPA was 3.41+/-0.13 (mean+/-SD) ng
ml(-1). This is the first demonstration as to what BPA concentrations
are in human colostrum. The BPA concentrations in colostrum were higher
than those in blood sera samples obtained from healthy women in a
previous study. In our study, there was no significant correlation
between the concentrations of BPA in colostrum and the age and parity
of mothers.
8. Assessment of human contamination of estrogenic endocrine-disrupting chemicals and their risk for human reproduction.
Tsutsumi O. J Steroid Biochem Mol Biol. 2005 93(2-5):325-30.
There is broad human exposure to estrogenic endocrine-disrupting
chemicals (EDCs), but the data sets that exist are primarily for
various environmental media such as food and water rather than the most
relevant internal exposure. We have detected various kind of EDC
contamination in humans including dioxin and bisphenol A (BPA) widely
used for the production of plastic products. BPA was present in serum
and follicular fluid at approximately 1-2 ng/ml, as well as in fetal
serum and full-term amniotic fluid, confirming passage through the
placenta. An approximately five-fold higher concentration, 8.3+/-8.7
ng/ml, was revealed in amniotic fluid at 15-18 weeks of gestation,
compared to other fluids showing increased exposure at the critical
developmental period in humans. Interestingly, serum BPA concentrations
were significantly higher in normal men and in women with polycystic
ovary syndrome (PCOS) compared with normal women possibly due to
differences in the androgen-related metabolism of BPA. These findings
may provide some insight into the metabolism of EDCs in human and the
pathophysiology of endocrine disorders such as PCOS. Dioxin
contamination in relationship to development of endometriosis is also
discussed.
9. Development and function of naturally occurring CD4+CD25+ regulatory T cells.
Toda A, Piccirillo CA. J Leukoc Biol. 2006 80(3):458-70.
{free online} http://www.jleukbio.org/cgi/content/full/80/3/458
10. Naturally occurring self-reactive CD4+CD25+ regulatory T cells: universal immune code.
Pakravan N et al. Cell Mol Immunol. 2007 4(3):197-201.
{free online} http://www.cmi.ustc.edu.cn/4/3/197.pdf
11. CD4+CD25+Foxp3+ regulatory T cells: from basic research to potential therapeutic use.
Mottet C, Golshayan D. Swiss Med Wkly. 2007 Nov 17;137(45-46):625-34.
{free online}
http://www.smw.ch/docs/pdf200x/2007/45/smw-11916.pdf
12. Exposure to bisphenol A during embryonic/fetal life and infancy
increases oxidative injury and causes underdevelopment of the brain and
testis in mice.
Kabuto H et al. Life Sci. 2004 74(24):2931-40.
We investigated the modifications in endogenous antioxidant capacity
and oxidative damage in the brain, liver, kidney and testis in mice
exposed to bisphenol A (BPA), an environmental endocrine disrupter.
Mice were exposed to BPA throughout embryonic/fetal life and during
lactation by feeding their pregnant/lactating mothers BPA at 5 or 10
microg per milliliter of drinking water. At the age of four weeks, male
mice were sacrificed. Exposure to BPA increased the activity of
catalase and glutathione peroxidase in the liver and kidney,
respectively. It also increased thiobarbituric acid-reactive substances
in the brain, kidney and testis, and decreased the wet weight of the
brain, kidney and testis. Our results suggest that exposure to BPA
throughout embryonic/fetal life and during infancy induces tissue
oxidative stress and peroxidation, ultimately leading to
underdevelopment of the brain, kidney and testis.
13. Effects of bisphenol A on the metabolisms of active oxygen species in mouse tissues.
Kabuto H et al. Environ Res. 2003 Sep;93(1):31-5.
We investigated the modifications in endogenous antioxidant capacity,
including superoxide dismutase (SOD), glutathione peroxidase (GPx),
catalase, oxidative stress index, reduced glutathione (GSH),
glutathione disulfide (GSSG), and thiobarbituric acid-reactive
substance (TBARS) in the brain, liver, kidney, and testes of mice under
bisphenol A (BPA), an endocrine disrupter, treated for 5 days. BPA was
administrated intraperitoneally at doses of 25 and 50mg/kg/day. The
TBARS levels were not affected by BPA administrations. The SOD
activities increased and the catalase activities decreased in the liver
after BPA administration. The GPx activity decreased in the kidney. The
levels of GSH+GSSG increased in the brain, kidney, liver, and testes,
while, the levels of GSH decreased in the testes. SOD converts
superoxide into hydrogen peroxide, and catalase and GPx convert
hydrogen peroxide into hydrogen oxide. Our results suggest that the
injection of BPA induces overproduction of hydrogen peroxide in the
mouse organs. Hydrogen peroxide is easily converted to hydroxy radical.
The decrease of GSH and the increase of GSSG may be caused by the
hydroxy radical. BPA may show its toxicity by increasing hydrogen
peroxide.
14. Glutathione S-transferase polymorphisms and their biological consequences.
Hayes JD, Strange RC. Pharmacology. 2000 Sep;61(3):154-66.
Two supergene families encode proteins with glutathione S-transferase
(GST) activity: the family of soluble enzymes comprises at least 16
genes; the separate family of microsomal enzymes comprises at least 6
genes. These two GST families are believed to exert a critical role in
cellular protection against oxidative stress and toxic foreign
chemicals. They detoxify a variety of electrophilic compounds,
including oxidized lipid, DNA and catechol products generated by
reactive oxygen species-induced damage to intracellular molecules. An
increasing number of GST genes are being recognized as polymorphic.
Certain alleles, particularly those that confer impaired catalytic
activity (e.g. GSTM1(*)0, GSTT1(*)0), may be associated with increased
sensitivity to toxic compounds. GST polymorphisms may be disease
modifying; for example, in subgroups of patients with basal cell
carcinoma or bronchial hyper-responsiveness, certain GST appear to
exert a statistically significant and biologically relevant impact on
disease susceptibility.
15. Homozygous gene deletions of the glutathione S-transferases M1 and T1 are associated with thimerosal sensitization.
Westphal GA et al. Int Arch Occup Environ Health. 2000 Aug;73(6):384-8.
16. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism.
James SJ et al. Am J Med Genet B Neuropsychiatr Genet. 2006 141B(8):947-56.
{free online}
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2610366&blobtype=pdf
Autism is a behaviorally defined neurodevelopmental disorder usually
diagnosed in early childhood that is characterized by impairment in
reciprocal communication and speech, repetitive behaviors, and social
withdrawal. Although both genetic and environmental factors are thought
to be involved, none have been reproducibly identified. The metabolic
phenotype of an individual reflects the influence of endogenous and
exogenous factors on genotype. As such, it provides a window through
which the interactive impact of genes and environment may be viewed and
relevant susceptibility factors identified. Although abnormal
methionine metabolism has been associated with other neurologic
disorders, these pathways and related polymorphisms have not been
evaluated in autistic children. Plasma levels of metabolites in
methionine transmethylation and transsulfuration pathways were measured
in 80 autistic and 73 control children. In addition, common polymorphic
variants known to modulate these metabolic pathways were evaluated in
360 autistic children and 205 controls. The metabolic results indicated
that plasma methionine and the ratio of S-adenosylmethionine (SAM) to
S-adenosylhomocysteine (SAH), an indicator of methylation capacity,
were significantly decreased in the autistic children relative to
age-matched controls. In addition, plasma levels of cysteine,
glutathione, and the ratio of reduced to oxidized glutathione, an
indication of antioxidant capacity and redox homeostasis, were
significantly decreased. Differences in allele frequency and/or
significant gene-gene interactions were found for relevant genes
encoding the reduced folate carrier (RFC 80G > 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}
http://archpedi.ama-assn.org/cgi/content/full/161/4/356
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}
http://www.jstage.jst.go.jp/article/endocrj/51/2/51_165/_article
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, respectively) and
obese normal women (1.04 +/- 0.09 ng/ml, p<0.05) compared with those
in non-obese normal women (0.71 +/- 0.09 ng/ml). There was no
difference among women with hyperprolactinemia, women with hypothalamic
amenorrhea, and non-obese normal women. There were significant positive
correlations between serum BPA and total testosterone (r = 0.391,
p<0.001), free testosterone (r = 0.504, p<0.001), androstenedione
(r = 0.684, p<0.001), and DHEAS (r = 0.514, p<0.001)
concentrations in all subjects. These findings show that there is a
strong relationship between serum BPA and androgen concentrations,
speculatively due to the effect of androgen on the metabolism of BPA.
20. Elevated serum bisphenol A levels under hyperandrogenic conditions
may be caused by decreased UDP-glucuronosyltransferase activity.
Takeuchi T et al. Endocr J. 2006 53(4):485-91.
{free online}
http://www.jstage.jst.go.jp/article/endocrj/53/4/53_485/_article
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.
21. Serum bisphenol a concentrations showed gender differences, possibly linked to androgen levels.
Takeuchi T, Tsutsumi O. Biochem Biophys Res Commun. 2002 291(1):76-8.
To investigate human exposure to bisphenol A (BPA), a widely used
endocrine disruptor, we measured serum BPA concentrations and analyzed
the interrelation of BPA with sex-related hormones. BPA was detected in
all human sera by a novel enzyme-linked immunosorbent assay. Serum BPA
concentrations were significantly higher in normal men (1.49 +/- 0.11
ng/ml; P < 0.01) and in women with polycystic ovary syndrome (1.04
+/- 0.10 ng/ml; P < 0.05) compared with normal women (0.64 +/- 0.10
ng/ml). There were significant positive correlations between serum BPA
and total testosterone (r = 0.595, P < 0.001) and free testosterone
(r = 0.609, P < 0.001) concentrations in all subjects and likewise
between serum BPA and total testosterone (r = 0.559, P < 0.01) and
free testosterone (r = 0.598, P < 0.001) concentrations in all
female subjects, but not between serum BPA and other sex-related
hormone concentrations in any group. These findings showed that there
are gender differences in serum BPA concentrations, possibly due to
differences in the androgen-related metabolism of BPA.
22. A clinical and laboratory evaluation of methionine
cycle-transsulfuration and androgen pathway markers in children with
autistic disorders.
Geier DA, Geier MR. Horm Res. 2006;66(4):182-8.
BACKGROUND/AIMS: The prevalence of autism spectrum disorders (ASDs) is
1 in 300 children in the US. ASDs are characterized by impairments in
social relatedness and communication, repetitive behaviors, abnormal
movement patterns, and sensory dysfunction. Pre-pubertal age children
with ASDs were assessed for metabolites in the methionine
cycle-transsulfuration and androgen pathways, and for present physical
development/behaviors indicative of hyperandrogenicity. METHODS: The
Institutional Review Board of the Institute for Chronic Illnesses
(Office for Human Research Protections, US Department of Health and
Human Services IRB number: IRB00005375) approved the present study.
Sixteen consecutive pre-pubertal age children (
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}
http://www.jleukbio.org/cgi/content/full/81/1/144
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}
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2266004&blobtype=pdf
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}
http://www.jneuroinflammation.com/content/5/1/52
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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