Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
December 17, 2009
Hypomethylation is
associated with autistic children and with their parents (1-3).
Bisphenol A (BPA) has been linked with hypomethylation (4). BPA may be
etiologically significant (and not necessarily the only causal factor)
in some cases of autism and schizophrenia (5).
Infants detoxify bisphenol A far less efficiently than do adults and,
as a result, have higher BPA levels (6-7).
Glucuronidation of BPA occurs via the human gene know as UGT2B15 (8),
whose polymorphisms may contribute inter-individual variability of BPA
levels and clearance in humans (eg, 9-11).
Preliminary conclusion: Intra-body BPA may be contribute to
hypomethylation found in some autistic children and in some parents of
autistic children and may be etiologically significant in some cases of
schizophrenia.
See also, Vaccination-induced cytokines: schizophrenia
& developmental disabilities
here.
References:
1. Metabolic
biomarkers of increased oxidative stress and impaired methylation
capacity in children with autism
James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW,
Neubrander JA.
Arkansas Children's Hospital Research Institute
Am J Clin Nutr. 2004 Dec;80(6):1611-7.
http://www.ajcn.org/cgi/reprint/80/6/1611
BACKGROUND: Autism is a complex neurodevelopmental disorder that
usually presents in early childhood and that is thought to be
influenced by genetic and environmental factors. Although abnormal
metabolism of methionine and homocysteine has been associated with
other neurologic diseases, these pathways have not been evaluated in
persons with autism. OBJECTIVE: The purpose of this study was to
evaluate plasma concentrations of metabolites in the methionine
transmethylation and transsulfuration pathways in children diagnosed
with autism. DESIGN: Plasma concentrations of methionine,
S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), adenosine,
homocysteine, cystathionine, cysteine, and oxidized and reduced
glutathione were measured in 20 children with autism and in 33 control
children. On the basis of the abnormal metabolic profile, a targeted
nutritional intervention trial with folinic acid, betaine, and
methylcobalamin was initiated in a subset of the autistic children.
RESULTS: Relative to the control children, the children with autism had
significantly lower baseline plasma concentrations of methionine, SAM,
homocysteine, cystathionine, cysteine, and total glutathione and
significantly higher concentrations of SAH, adenosine, and oxidized
glutathione. This metabolic profile is consistent with impaired
capacity for methylation (significantly lower ratio of SAM to SAH) and
increased oxidative stress (significantly lower redox ratio of reduced
glutathione to oxidized glutathione) in children with autism. The
intervention trial was effective in normalizing the metabolic imbalance
in the autistic children. CONCLUSIONS: An increased vulnerability to
oxidative stress and a decreased capacity for methylation may
contribute to the development and clinical manifestation of autism.
2. 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 Dec 5;141B(8):947-56.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2610366/pdf/nihms68264.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.
3. Abnormal
transmethylation/transsulfuration metabolism and DNA hypomethylation
among parents of children with autism
James SJ, Melnyk S, Jernigan S, Hubanks A, Rose S, Gaylor DW.
University of Arkansas for Medical Sciences
J Autism Dev Disord. 2008 Nov;38(10):1966-75.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2584168/pdf/nihms-51702.pdf
An integrated metabolic profile reflects the combined influence of
genetic, epigenetic, and environmental factors that affect the
candidate pathway of interest. Recent evidence suggests that some
autistic children may have reduced detoxification capacity and may be
under chronic oxidative stress. Based on reports of abnormal methionine
and glutathione metabolism in autistic children, it was of interest to
examine the same metabolic profile in the parents. The results
indicated that parents share similar metabolic deficits in methylation
capacity and glutathione-dependent antioxidant/detoxification capacity
observed in many autistic children. Studies are underway to determine
whether the abnormal profile in parents reflects linked genetic
polymorphisms in these pathways or whether it simply reflects the
chronic stress of coping with an autistic child.
4. Maternal nutrient
supplementation counteracts bisphenol A-induced DNA hypomethylation in
early development
Dolinoy DC, Huang D, Jirtle RL.
Duke University
Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13056-61. Epub 2007 Aug
1.
http://www.pnas.org/content/104/32/13056.long
The hypothesis of fetal origins of adult disease posits that early
developmental exposures involve epigenetic modifications, such as DNA
methylation, that influence adult disease susceptibility. In utero or
neonatal exposure to bisphenol A (BPA), a high-production-volume
chemical used in the manufacture of polycarbonate plastic, is
associated with higher body weight, increased breast and prostate
cancer, and altered reproductive function. This study shows that
maternal exposure to this endocrine-active compound shifted the coat
color distribution of viable yellow agouti (Avy) mouse offspring toward
yellow by decreasing CpG (cytosine-guanine dinucleotide) methylation in
an intracisternal A particle retrotransposon upstream of the Agouti
gene. CpG methylation also was decreased at another metastable locus,
the CDK5 activator-binding protein (CabpIAP). DNA methylation at the
Avy locus was similar in tissues from the three germ layers, providing
evidence that epigenetic patterning during early stem cell development
is sensitive to BPA exposure. Moreover, maternal dietary
supplementation, with either methyl donors like folic acid or the
phytoestrogen genistein, negated the DNA hypomethylating effect of BPA.
Thus, we present compelling evidence that early developmental exposure
to BPA can change offspring phenotype by stably altering the epigenome,
an effect that can be counteracted by maternal dietary supplements.
5. Effects of
bisphenol-A and other endocrine disruptors compared with abnormalities
of schizophrenia: an endocrine-disruption theory of
schizophrenia
Brown JS Jr.
Department of Psychiatry, VCU School of Medicine, Richmond, VA, USA. jbrown2185@aol.com
Schizophr Bull. 2009 Jan;35(1):256-78. Epub 2008 Jan 31.
http://schizophreniabulletin.oxfordjournals.org/cgi/reprint/35/1/256
In recent years, numerous substances have been identified as so-called
"endocrine disruptors" because exposure to them results in disruption
of normal endocrine function with possible adverse health outcomes. The
pathologic and behavioral abnormalities attributed to exposure to
endocrine disruptors like bisphenol-A (BPA) have been studied in
animals. Mental conditions
ranging from cognitive impairment to autism have been linked to BPA
exposure by more than one investigation.
Concurrent with these developments in BPA research, schizophrenia
research has continued to find evidence of possible endocrine or
neuroendocrine involvement in the disease. Sufficient information now
exists for a comparison of the neurotoxicological and behavioral
pathology associated with exposure to BPA and other endocrine
disruptors to the abnormalities observed in schizophrenia. This review
summarizes these findings and proposes a theory of endocrine
disruption, like that observed from BPA exposure, as a pathway of
schizophrenia pathogenesis. The review shows similarities exist between
the effects of exposure to BPA and other related chemicals with
schizophrenia. These similarities can be observed in 11 broad
categories of abnormality: physical development, brain anatomy,
cellular anatomy, hormone function, neurotransmitters and receptors,
proteins and factors, processes and substances, immunology, sexual
development, social behaviors or physiological responses, and other
behaviors. Some of these similarities are sexually dimorphic and
support theories that sexual dimorphisms may be important to
schizophrenia pathogenesis. Research recommendations for further
elaboration of the theory are proposed.
6. Bisphenol A levels
in blood depend on age and exposure
Mielke H, Gundert-Remy U.
Federal Institute for Risk Assessment, Berlin, Germany
Toxicol Lett. 2009 Oct 8;190(1):32-40.
We present two approaches to estimate blood concentrations of Bisphenol
A (BPA). Simple kinetic principles were applied to calculate steady
state plasma concentrations. A physiologically based model was used to
simulate the blood concentration time profile in several age groups
exploring the influence of not yet fully developed metabolic capacity
on the blood concentrations in the newborn. Both approaches gave
concordant results and are in excellent agreement with experimental
results [Völkel, W., Colnot, T., Csanady, G.A., Filser, J.G., Dekant,
W., 2002. Metabolism and kinetics of bisphenol A in humans at low doses
following oral administration. Chem. Res. Toxicol. 15, 1281-1287]. The
predictions also agree with published results obtained with a different
physiologically based model. According to model simulations, BPA is
present in the blood of the normal population at concentrations several
orders of magnitude lower than most measurements reported in the
literature. At the same
external exposure level, the newborn is predicted to have 3 times
greater blood concentration than the adult. This is due to the not yet
fully developed glucuronidation activity in the newborn, not fully
compensated by the unimpaired sulfation pathway. For the highest measured external BPA exposure, the
predicted blood concentrations of 2.6 pg/ml (steady state
concentration) and 8.2 pg/ml (peak concentration) in the adult are
lower than the in vitro concentrations at which inhibiting adiponectin
release from human adipocytes and stimulation of beta-cell production
and secretion were observed.
7. Predicting plasma
concentrations of bisphenol A in children younger than 2 years of age
after typical feeding schedules, using a physiologically based
toxicokinetic model
Edginton AN, Ritter L.
Environ Health Perspect. 2009 Apr;117(4):645-52.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2679611/pdf/ehp-117-645.pdf
BACKGROUND: Concerns have recently been raised regarding the safety of
potential human exposure to bisphenol A (BPA), an industrial chemical
found in some polycarbonate plastics and epoxy resins. Of particular
interest is the exposure of young children to BPA via food stored in
BPA-containing packaging. OBJECTIVES: In this study we assessed the age
dependence of the toxicokinetics of BPA and its glucuronidated
metabolite, BPA-Glu, using a coupled BPA-BPA-Glu physiologically based
toxicokinetic (PBTK) model. METHODS: Using information gathered from
toxicokinetic studies in adults, we built a PBTK model. We then scaled
the model to children < 2 years of age based on the age dependence
of physiologic parameters relevant for absorption, distribution,
metabolism, and excretion. RESULTS: We estimated the average steady-state BPA plasma concentration
in newborns to be 11 times greater than that in adults when given the
same weight-normalized dose. Because of the rapid development of the
glucuronidation process, this ratio dropped to 2 by 3 months of age.
Simulation of typical feeding exposures, as estimated by regulatory
authorities, showed a 5-fold greater steady-state BPA plasma
concentration in 3- and 6-month-olds compared with adults, reflecting
both a reduced capacity for BPA metabolism and a greater
weight-normalized BPA exposure.Because of
uncertainty in defining the hepatic BPA intrinsic clearance in adults,
these values represent preliminary estimates. CONCLUSIONS: Simulations
of the differential BPA dosimetry between adults and young children
point to the need for more sensitive analytical methods for BPA to
define, with greater certainty, the adult hepatic BPA intrinsic
clearance, as well as a need for external exposure data in young
children.
8. Human
UDP-glucuronosyltransferase isoforms involved in bisphenol A
glucuronidation
Hanioka N, Naito T, Narimatsu S.
Chemosphere. 2008 Dec;74(1):33-6.
Bisphenol A (BPA) is one of a number of potential endocrine disruptors
which may affect normal hormonal function. In this study, human
UDP-glucuronosyltransferase (UGT) isoforms involved in BPA
glucuronidation were studied by kinetic analyses using human liver
microsomes and recombinant human UGTs... These findings demonstrate
that BPA is mainly
glucuronidated by UGT2B15 in human liver microsomes, and suggest that this UGT isoform plays important roles in
the detoxification and elimination of BPA.
9. UDP-glucuronosyltransferase (UGT) 2B15 pharmacogenetics:
UGT2B15 D85Y genotype and gender are major determinants of oxazepam
glucuronidation by human liver
Court MH et al.
Tufts University School of Medicine
J Pharmacol Exp Ther. 2004 Aug;310(2):656-65. Epub 2004 Mar 25.
http://jpet.aspetjournals.org/content/310/2/656.long
Oxazepam is a commonly used 1,4-benzodiazepine anxiolytic drug that is
polymorphically metabolized in humans. However, the molecular basis for
this phenomenon is currently unknown. We have previously shown that
S-oxazepam glucuronide, the major oxazepam metabolite, is selectively
formed by UDP-glucuronosyltransferase (UGT) 2B15, whereas the minor
R-oxazepam glucuronide is produced by multiple UGTs other than UGT2B15.
Phenotype-genotype studies were conducted using microsomes and DNA
prepared from the same set of 54 human livers. Sequencing of the
UGT2B15 gene revealed three nonsynonymous polymorphisms, D85Y, T352I,
and K523T, with variant allele frequencies of 0.56, 0.02, and 0.40,
respectively. D85Y genotype showed a significant effect (p = 0.012) on
S-oxazepam glucuronidation with lower median activities in 85Y/Y livers
(49 pmol/min/mg protein) compared with 85D/D livers (131 pmol/min/mg),
whereas 85D/Y livers were intermediate in activity (65 pmol/min/mg).
There was also a significant trend (p = 0.049) for higher S-oxazepam
activities in the two 352T/I livers (135 and 210 pmol/min/mg) compared
with the remaining 352T/T livers (median, 64 pmol/min/mg). Conversely,
K523T genotype had no apparent effect on oxazepam glucuronidation (p
> 0.05). Donor gender also significantly influenced S-oxazepam
glucuronidation with higher median activities in male (65 pmol/min/mg)
compared with female (39 pmol/min/ mg) livers (p = 0.042). R-Oxazepam
glucuronidation was not affected by either genotype or gender (p >
0.05). In conclusion, gender and D85Y genotype are identified as major
determinants of S-oxazepam glucuronidation by human liver and may
explain in part polymorphic oxazepam glucuronidation by human
subjects.
10. Polymorphism of
UDP-glucuronosyltransferase and drug
metabolism
Maruo Y, Iwai M, Mori A, Sato H, Takeuchi Y.
Curr Drug Metab. 2005 Apr;6(2):91-9.
UDP-glucuronosyltransferase is a group of catabolic enzymes involved in
the detoxification and excretion of many xenobiotic and endogeneous
substances in intrahepatic and extrahepatic tissues. The group consists
of two subfamilies, UGT1 and UGT2. UGT1 consists of 5 exons and has a
unique gene structure. There are thirteen exon 1s from UGT1A1 to
UGT1A13P, and exon 2 to exon 5 are used in common for all mRNAs
expressed from the gene. Each isoform of UGT1 results from differential
splicing of exon1s to common exon 2-5, and has an unique spectrum of
substrate specificity. In contrast, the genes of the UGT2 family
consist of 6 exons, and all the enzymes have an individual set of exon
1 to exon 6. In UGT1 there are no reports of polymorphism in the common
exons, although a number of polymorphisms have been reported for exon
1s. The mutations of UGT1A1 cause hereditary unconjugated
hyperbilirubinemias: Crigler-Najjar syndrome type I, type II and
Gilbert syndrome. UGT1A1 has two major polymorphisms--a missense
mutation of G71R and an insertion mutation of TATA box. Prevalence of
Gilbert syndrome is attributed to these polymorphisms. Since UGT1A1
metabolizes not only bilirubin but also hormones and drugs, the
mutations could be involved in carcinogenesis and adverse drug
reactions. Recent studies
also revealed a widespread presence of diverse polymorphisms in other
isoforms of UGT1 as well as the UGT2 family, including UGT1A6, UGTG1A7, UGT1A8, UGT1A10, UGT2B4, UGT2B7
and UGT2B15. The incidences and types
of the polymorphisms for these enzymes are quite different in region
and ethnic groups. Understanding of these polymorphisms is essential
for the prevention of adverse effects of a considerable number of drugs
and to predict cancer risks.
11. Effect of the
UGT2B15 genotype on the pharmacokinetics, pharmacodynamics, and drug
interactions of intravenous lorazepam in healthy
volunteers
Chung JY, Cho JY, Yu KS, Kim JR, Jung HR, Lim KS, Jang IJ, Shin SG.
Clin Pharmacol Ther. 2005 Jun;77(6):486-94.
OBJECTIVE: Our objective was to investigate the effect of the uridine
5'-diphosphate-glucuronosyltransferase (UGT) 2B15 genetic polymorphism
on the pharmacokinetics and pharmacodynamics of lorazepam in basal,
inhibited, and induced metabolic states in healthy normal volunteers.
METHODS: Twenty-four healthy subjects were enrolled and grouped into
UGT2B15*1/*1 or UGT2B15*2/*2 genotype groups. The pharmacokinetic and
pharmacodynamic profiles of intravenous lorazepam were characterized
before and after inhibition with 600 mg valproate once daily for 4 days
and after induction with rifampin (INN, rifampicin) pretreatment (600
mg once daily for 10 days), with a washout period of 10 days between.
The plasma concentrations of lorazepam and lorazepam glucuronide were
analyzed before and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 48
hours after lorazepam administration by liquid chromatography-tandem
mass spectrometry. Visual analog scale assessments and psychomotor
coordination tests were administered before and up to 12 hours after
drug administration. RESULTS: The UGT2B15*2/*2 group showed 0.58-fold
(95% confidence interval, 0.43-0.72; P < .0001) lower systemic
clearance during the basal state and 1.37-fold (95% confidence
interval, 1.05-1.88; P = .037) higher area under the visual analog
scale-time curve during the induced state compared with the
UGT2B15*1/*1 group. The mean systemic clearance of lorazepam decreased
by 20% in the inhibited state and increased by 140% in the induced
state. During the inhibited or induced state, absolute values of
clearance were consistently lower in the *2/*2 group, but the percent
changes from baseline did not differ significantly by genotype.
CONCLUSIONS: Our results
suggest that the UGT2B15*2 polymorphism is a major determinant of
interindividual variability with respect to the pharmacokinetics and
pharmacodynamics of lorazepam.
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