Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
May 11, 2009
The notion "better living
through chemistry" is fraught with irony. Organoclorines and similar
molecules are altering development and more in humans and other
species. Consider the findings of a Dutch study in published in 2002:
"Effects of prenatal exposure to PCBs, measured in maternal and cord
plasma, on the masculine and composite scales were different for boys
and girls... In boys, higher prenatal PCB levels were related with less
masculinized play... whereas in girls higher PCB levels were associated
with more masculinized play..." (1)
More recently, a primate study about early exposure to bisphenol A
(BPA) reported: "Prenatal exposure to BPA altered the behaviors of male
infants significantly; BPA-exposed male infants behaved as female
infants. And it also affected some of female infant behaviors." (2)
Relevance to autism is provided by findings describing autism-spectrum
disorders regarding maternal proximity to agricultural organochlorines,
wherein the researchers concluded, "ASD risk increased with the
poundage of organochlorine applied and decreased with distance from
field sites." (3) Other findings regarding ASDs and pollutants were
reported by Windham et al, who concluded that "The individual compounds
that contributed most to these associations included mercury, cadmium,
nickel, trichloroethylene, and vinyl chloride." (4)
These several citations and others (eg, 5-8, 18) make clear that
exposure to pollutants is affecting central nervous system development
in human children, with effects ranging from gender-behavior
alterations to autism-spectrum disorders including autism. Amid these
findings is inter-individual variability, which can derive from
different exposures and from polymorphisms (variants) in genes related
to detoxification (eg, 7, 9-11). Relevance to autism and other ASDs is
documented by the work of Westphal et al and James et al, who describe
glutathione-enzyme variants in relation to thimerosal (eg, 12-13).
Furthermore, humans are born with a large number of intra-body
pollutants (high body burden; 14), and detoxification of many of those
pollutants can be impaired by thimerosal, which inhibits expression of
a crucial enzyme related to glutathione (15).
This brief essay calls attention to two studies about how sexual
differentiation of the human brain is being changed by patented
chemicals which become intra-body pollutants (1-2). The processes
identified in these studies occur in a larger context of pollutants
associated with autism and other ASDs. The relevance of endocrine
disrupting chemicals' (EDCs) effects upon humans is reinforced, for
instance, by studies documenting the presence of bisphenol A in human
tissues (eg, 16-18; see also 19).
In April of 2010, two new
studies affirm how chemicals are altering development of human brains
(20-21).
References:
1. Effects of perinatal exposure to PCBs and dioxins on play behavior
in Dutch children at school age
Vreugdenhil HJ, Slijper FM, Mulder PG, Weisglas-Kuperus N.
Environ Health Perspect. 2002 Oct;110(10):A593-8.
http://www.ehponline.org/members/2002/110pA593-A598vreugdenhil/vreugdenhil-full.html
Polychlorinated biphenyls (PCBs) and dioxins are known as neurotoxic
compounds that may modulate sex steroid hormones. Steroid hormones play
a mediating role in brain development and may influence behaviors that
show sex differences, such as childhood play behavior. In this study we
evaluated the effects of perinatal exposure to environmental levels of
PCBs and dioxins on childhood play behavior and whether the effects
showed sex differences. As part of the follow-up to the Dutch
PCB/dioxin study at school age, we used the Pre-School Activity
Inventory (PSAI) to assess play behavior in the Rotterdam cohort (n =
207). The PSAI assesses masculine or feminine play behavior scored on
three subscales: masculine, feminine, and composite. Prenatal exposure
to PCBs was defined as the sum of PCB 118, 138, 153, and 180 in
maternal and cord plasma and breast milk. For breast milk we measured
additional PCBs as well as 17 dioxins. Respondents returned 160
questionnaires (age 7.5 years +/- 0.4). Effects of prenatal exposure to
PCBs, measured in maternal and cord plasma, on the masculine and
composite scales were different for boys and girls (p <.05). In
boys, higher prenatal PCB levels were related with less masculinized
play, assessed by the masculine scale (p(maternal) =.042; p(cord)
=.001) and composite scale (p(cord) =.011), whereas in girls higher PCB
levels were associated with more masculinized play, assessed by the
composite scale (p(PCBmilk) =.028). Higher prenatal dioxin levels were
associated with more feminized play in boys as well as girls, assessed
by the feminine scale (p =.048). These effects suggest prenatal steroid
hormone imbalances caused by prenatal exposure to environmental levels
of PCBs, dioxins, and other related organochlorine compounds.
2. Alterations in male infant behaviors towards its mother by prenatal
exposure to bisphenol A in cynomolgus monkeys (Macaca fascicularis)
during early suckling period
Nakagami A et al.
Psychoneuroendocrinology Article in Press, Corrected Proof 2009
http://tinyurl.com/qqmuh7
Bisphenol A (BPA) is an environmental chemical with physiological
potencies that cause adverse effects, even at environmentally relevant
exposures, on the basis of a number of studies in experimental rodents.
Thus, there is an increasing concern about environmental exposure of
humans to BPA. In the present study, we used experimentally controlled
cynomolgus monkeys (Macaca fascicularis) to assess the influence of
prenatal exposure to BPA (10 μg/(kg day)) via subcutaneously
implanted pumps and examined social behaviors between infants and their
mothers during the suckling period. Mother–infant interactions in
cynomolgus monkeys had behavioral sexual dimorphism associated with sex
of infant from early suckling period. Prenatal exposure to BPA altered
the behaviors of male infants significantly; BPA-exposed male infants
behaved as female infants. And it also affected some of female infant
behaviors. Consequently, gestational BPA exposure altered some
behaviors of their mothers, mainly in male-nursing mothers. These
results suggest that BPA exposure affects behavioral sexual
differentiation in male monkeys, which promotes the understanding of
risk of BPA exposure in human.
3. Maternal residence near agricultural pesticide applications and
autism spectrum disorders among children in the California Central
Valley.
Roberts EM et al.
Environ Health Perspect. 2007 Oct;115(10):1482-9.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2022638&blobtype=pdf
BACKGROUND: Ambient levels of pesticides ("pesticide drift") are
detectable at residences near agricultural field sites. OBJECTIVE: Our
goal was to evaluate the hypothesis that maternal residence near
agricultural pesticide applications during key periods of gestation
could be associated with the development of autism spectrum disorders
(ASD) in children. METHODS: We identified 465 children with ASD born
during 1996-1998 using the California Department of Developmental
Services electronic files, and matched them by maternal date of last
menstrual period to 6,975 live-born, normal-birth-weight, term infants
as controls. We determined proximity to pesticide applications using
California Department of Pesticide Regulation records refined using
Department of Water Resources land use polygons. A staged analytic
design applying a priori criteria to the results of conditional
logistic regressions was employed to exclude associations likely due to
multiple testing error. RESULTS: Of 249 unique hypotheses, four that
described organochlorine pesticide applications--specifically those of
dicofol and endosulfan--occurring during the period immediately before
and concurrent with central nervous system embryogenesis (clinical
weeks 1 through 8) met a priori criteria and were unlikely to be a
result of multiple testing. Multivariate a posteriori models comparing
children of mothers living within 500 m of field sites with the highest
nonzero quartile of organochlorine poundage to those with mothers not
living near field sites suggested an odds ratio for ASD of 6.1 (95%
confidence interval, 2.4-15.3). ASD risk increased with the poundage of
organochlorine applied and decreased with distance from field sites.
CONCLUSIONS: The association between residential proximity to
organochlorine pesticide applications during gestation and ASD among
children should be further studied.
4. Autism spectrum disorders in relation to distribution of hazardous
air pollutants in the san francisco bay area.
Windham GC et al.
Environ Health Perspect. 2006 Sep;114(9):1438-44.
http://www.ehponline.org/members/2006/9120/9120.html
OBJECTIVE: To explore possible associations between autism spectrum
disorders (ASD) and environmental exposures, we linked the California
autism surveillance system to estimated hazardous air pollutant (HAP)
concentrations compiled by the U.S. Environmental Protection Agency.
METHODS: Subjects included 284 children with ASD and 657 controls, born
in 1994 in the San Francisco Bay area. We assigned exposure level by
census tract of birth residence for 19 chemicals we identified as
potential neurotoxicants, developmental toxicants, and/or endocrine
disruptors from the 1996 HAPs database. Because concentrations of many
of these were highly correlated, we combined the chemicals into
mechanistic and structural groups, calculating summary index scores. We
calculated ASD risk in the upper quartiles of these group scores or
individual chemical concentrations compared with below the median,
adjusting for demographic factors. RESULTS: The adjusted odds ratios
(AORs) were elevated by 50% in the top quartile of chlorinated solvents
and heavy metals [95% confidence intervals (CIs) , 1.1-2.1], but not
for aromatic solvents. Adjusting for these three groups simultaneously
led to decreased risks for the solvents and increased risk for metals
(AORs for metals: fourth quartile = 1.7 ; 95% CI, 1.0-3.0 ; third
quartile = 1.95 ; 95% CI, 1.2-3.1) . The individual compounds that
contributed most to these associations included mercury, cadmium,
nickel, trichloroethylene, and vinyl chloride. CONCLUSIONS: Our results
suggest a potential association between autism and estimated metal
concentrations, and possibly solvents, in ambient air around the birth
residence, requiring confirmation and more refined exposure assessment
in future studies.
5. Proximity to point sources of environmental mercury release as a
predictor of autism prevalence.
Palmer RF, Blanchard S, Wood R.
Health Place. 2009 Mar;15(1):18-24. Epub 2008 Feb 12.
http://images.huffingtonpost.com/2009-01-29-Palmer2008.pdf
The objective of this study was to determine if proximity to sources of
mercury pollution in 1998 were related to autism prevalence in 2002.
Autism count data from the Texas Educational Agency and environmental
mercury release data from the Environmental Protection Agency were
used. We found that for every 1000 pounds of industrial release, there
was a corresponding 2.6% increase in autism rates (p<.05) and a 3.7%
increase associated with power plant emissions(P<.05). Distances to
these sources were independent predictors after adjustment for relevant
covariates. For every 10 miles from industrial or power plant sources,
there was an associated decreased autism Incident Risk of 2.0% and
1.4%, respectively (p<.05). While design limitations preclude
interpretation of individual risk, further investigations of
environmental risks to child development issues are warranted.
6. Environmental mercury release, special education rates, and autism
disorder: an ecological study of Texas.
Palmer RF, Blanchard S, Stein Z, Mandell D, Miller C.
Health Place. 2006 Jun;12(2):203-9.
http://www.generationrescue.org/pdf/seed.pdf
The association between environmentally released mercury, special
education and autism rates in Texas was investigated using data from
the Texas Education Department and the United States Environmental
Protection Agency. A Poisson regression analysis adjusted for school
district population size, economic and demographic factors was used.
There was a significant increase in the rates of special education
students and autism rates associated with increases in environmentally
released mercury. On average, for each 1,000 lb of environmentally
released mercury, there was a 43% increase in the rate of special
education services and a 61% increase in the rate of autism. The
association between environmentally released mercury and special
education rates were fully mediated by increased autism rates. This
ecological study suggests the need for further research regarding the
association between environmentally released mercury and developmental
disorders such as autism. These results have implications for policy
planning and cost analysis.
7. Paraoxonase gene variants are associated with autism in North
America, but not in Italy: possible regional specificity in
gene-environment interactions.
D'Amelio M et al.
Mol Psychiatry. 2005 Nov;10(11):1006-16.
Organophosphates (OPs) are routinely used as pesticides in agriculture
and as insecticides within the household. Our prior work on Reelin and
APOE delineated a gene-environment interactive model of autism
pathogenesis, whereby genetically vulnerable individuals prenatally
exposed to OPs during critical periods in neurodevelopment could
undergo altered neuronal migration, resulting in an autistic syndrome.
Since household use of OPs is far greater in the USA than in Italy,
this model was predicted to hold validity in North America, but not in
Europe. Here, we indirectly test this hypothesis by assessing
linkage/association between autism and variants of the paraoxonase gene
(PON1) encoding paraoxonase, the enzyme responsible for OP
detoxification. Three functional single nucleotide polymorphisms, PON1
C-108T, L55M, and Q192R, were assessed in 177 Italian and 107
Caucasian-American complete trios with primary autistic probands. As
predicted, Caucasian-American and not Italian families display a
significant association between autism and PON1 variants less active in
vitro on the OP diazinon (R192), according to case-control contrasts
(Q192R: chi2=6.33, 1 df, P<0.025), transmission/disequilibrium tests
(Q192R: TDT chi2=5.26, 1 df, P<0.025), family-based association
tests (Q192R and L55M: FBAT Z=2.291 and 2.435 respectively,
P<0.025), and haplotype-based association tests (L55/R192: HBAT
Z=2.430, P<0.025). These results are consistent with our model and
provide further support for the hypothesis that concurrent genetic
vulnerability and environmental OP exposure may possibly contribute to
autism pathogenesis in a sizable subgroup of North American
individuals.
8. Hepatitis B triple series vaccine and developmental disability in US
children aged 1-9 years
Carolyn Gallagher ; Melody Goodman
Toxicological & Environmental Chemistry 2008 90(5):997 - 1008.
This study investigated the association between vaccination with the
Hepatitis B triple series vaccine prior to 2000 and developmental
disability in children aged 1-9 years (n = 1824), proxied by parental
report that their child receives early intervention or special
education services (EIS). National Health and Nutrition Examination
Survey 1999-2000 data were analyzed and adjusted for survey design by
Taylor Linearization using SAS version 9.1 software, with SAS callable
SUDAAN version 9.0.1. The odds of receiving EIS were approximately nine
times as great for vaccinated boys (n = 46) as for unvaccinated boys (n
= 7), after adjustment for confounders. This study found statistically
significant evidence to suggest that boys in United States who were
vaccinated with the triple series Hepatitis B vaccine, during the time
period in which vaccines were manufactured with thimerosal, were more
susceptible to developmental disability than were unvaccinated boys.
9. Diet, genetic polymorphisms, detoxification, and health risks.
Lampe JW.
Altern Ther Health Med. 2007 Mar-Apr;13(2):S108-11.
Modulation of detoxification enzymes is one mechanism by which diet may
influence risk of cancer and other diseases. However, genetic
differences in taste preference, food tolerance, nutrient absorption,
and metabolism and response of target tissues all potentially influence
the effect of diet on disease risk. Thus, disease prevention at the
individual and population level needs to be evaluated in the context of
the totality of genetic background and exposures to both causative
agents and chemopreventive compounds. Polymorphisms in the
detoxification enzymes that alter protein expression and/or function
can modify risk in individuals exposed to the relevant substrates. Diet
is a mixture of carcinogens, mutagens, and protective agents that are
all metabolized by detoxification enzymes. Genotypes associated with
more favorable handling of carcinogens may be associated with less
favorable handling of phytochemicals. For example, glutathione
S-transferases (GST) detoxify polycyclic aromatic hydrocarbons present
in grilled meats. GSTs also conjugate isothiocyanates, the
chemopreventive compounds found in cruciferous vegetables.
Polymorphisms in the GSTM1 and GSTT1 genes result in complete lack of
GSTM1-1 and GSTT1-1 proteins, respectively. In some observational
studies of cancer, cruciferous vegetable intake confers greater
protection in individuals with these polymorphisms; however, in other
studies, the converse is observed. A recent study of sulforaphane
pharmacokinetics suggests that lack of the GSTM1 enzyme is associated
with more rapid excretion of sulforaphane. Many phytochemicals are also
conjugated with glucuronide and sulfate moieties, and are excreted in
urine and bile. Polymorphisms in UDP-glucuronosyltransferases (UGT) and
sulfotransferases (SULT) may contribute to the variability in
phytochemical clearance and efficacy. The effects of UGT polymorphisms
on flavonoid clearance have not been examined, but UGT polymorphisms
affect glucuronidation of several drugs and steroid hormones. Genetic
polymorphisms in detoxification enzymes may account in part for
individual variation in disease risk but have to be considered in the
context of other aspects of human genetics, gut bacterial genetics, and
environmental exposures.
10. Past and future applications of CYP450-genetic polymorphisms for
biomonitoring of environmental toxicants.
Yi B, Yang JY, Yang M.
J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2007
Oct-Dec;25(4):353-77.
Cytochrome P450s (CYPs) are a huge gene superfamily of heme enzymes
involved in xenobioitc as well as endobiotic metabolism. They play a
critical role in adaptation to environmental changes for survival of
living organisms. In addition, the huge environmental loads of
human-made chemicals are biotransformed into bioactive or detoxified
forms by CYPs. Thus, CYPs have been used for biomonitoring of
environmental pollutants, screening of their metabolisms and exploring
remedy. In particular, the induction or inhibition of CYPs has been
applied to exposure monitoring of environmental toxicants, which are
biotransformed by CYPs. This review considers past and future
applications of CYP-genetic polymorphisms as susceptibility biomarkers
for biomonitoring. Furthermore, we suggest the needs for further
understanding of the characteristics of each CYP isozyme, consideration
of real-life exposures such as mixed contamination with various
chemicals, and incorporation of the presence of other phase I and phase
II enzymes, for proper applications of CYP polymorphisms on
biomonitoring.
11. Polymorphic variations in the expression of the chemical
detoxifying UDP glucuronosyltransferases.
Mackenzie PI et al.
Toxicol Appl Pharmacol. 2005 Sep 1;207(2 Suppl):77-83.
The UDP glucuronosyltransferases (UGT) are expressed predominantly in
the liver and gastrointestinal tract in humans. Their expression varies
widely between individuals, due in part to coding region polymorphisms
that alter catalytic function and in part, to differences in the
regulation of UGT genes. The latter differences are most likely the
result of polymorphisms in the regulatory elements of UGT genes and in
the transcription factors that bind to these elements. Several frequent
polymorphisms in the promoters of UGT genes have been described;
however, few of these fall within critical regulatory elements and
alter UGT expression. Some rare mutations alter UGT promoter activity
in in vitro systems but their effect in the clinic is still to be
confirmed. Several transcription factors that regulate UGT gene
expression in cells of hepatic and intestinal origin have been
identified. These include positive regulators of UGT gene expression
such as hepatocyte nuclear factor 1 alpha (HNF1 alpha), octamer
transcription factor-1 (Oct-1) and the intestine-specific transcription
factor, caudal-related homeodomain protein 2 (Cdx2). Negative
regulators include the Pre B cell homeobox factor (Pbx2) and its
dimerization partner, Pbx regulating protein 1 (Prep1). Polymorphisms
in these transcription factors may cause differences in their
interaction and binding to UGT promoters. Current work describing the
effects of these transcription factor polymorphisms on UGT expression
will be described. Knowledge of UGT promoter elements and the proteins
that bind to these elements, as well as knowledge of polymorphisms that
alter their function, may aid in the prediction of an individual's
response to chemicals and in the prediction of chemical toxicities.
12. 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.
OBJECTIVE: Thimerosal is an important preservative in vaccines and
ophthalmologic preparations. The substance is known to be a type IV
sensitizing agent. High sensitization rates were observed in
contact-allergic patients and in health care workers who had been
exposed to thimerosal-preserved vaccines. There is evidence for the
involvement of the glutathione system in the metabolism of thimerosal
or its decomposition products (organomercury alkyl compounds). Thus
detoxification by polymorphically expressed glutathione S-transferases
such as GSTT1 and GSTM1 might have a protective effect against
sensitization by these substances. METHODS: To address this question, a
case control study was conducted, including 91 Central European
individuals with a positive patch-test reaction to thimerosal. This
population was compared with 169 healthy controls and additionally with
114 individuals affected by an allergy against para-substituted aryl
compounds. The latter population was included in order to test whether
possible associations were due to substance-specific effects, or were a
general feature connected with type IV immunological diseases.
Homozygous deletions of GSTT1 and GSTM1 were determined by polymerase
chain reaction. RESULTS: Glutathione S-transferase M1 deficiency was
significantly more frequent among patients sensitized to thimerosal
(65.9%, P = 0.013) compared with the healthy control group (49.1%) and
the "para-compound" group (48%, P = 0.034). Glutathione S-transferase
T1 deficiency in the thimerosal/mercury group (19.8%) was barely
elevated versus healthy controls (16.0%) and the "para-compound" group
(14.0%). The combined deletion (GSTT1-/GSTM1-) was markedly more
frequent among thimerosal-sensitized patients than in healthy controls
(17.6% vs. 6.5%, P = 0.0093) and in the "para-compound" group (17.6%
vs. 6.1%, P =0.014), revealing a synergistic effect of these enzyme
deficiencies (healthy controls vs. thimerosal GSTM1 negative
individuals, OR = 2.0 [CI = 1.2-3.4], GSTT1-, OR = 1.2 [CI = 0.70-2.1],
GSTM1/T1-, OR = 3.1 [CI = 1.4-6.5]). CONCLUSIONS: Since the
glutathione-dependent system was repeatedly shown to be involved in the
metabolism of thimerosal decomposition products, the observed
association may be of functional relevance.
13. 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.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.
14. The pollution in newborns.
http://archive.ewg.org/reports/bodyburden2/statement.php
15. Inhibition of the human erythrocytic glutathione-S-transferase T1
(GST T1) by thimerosal.
Müller M, Westphal G, Vesper A, Bünger J, Hallier E.
Int J Hyg Environ Health. 2001 Jul;203(5-6):479-81.
We have investigated the interaction of thimerosal, a widely used
antiseptic and preservative, with the human erythrocytic GST T1
(glutathione-S-transferase T1). This detoxifying enzyme is expressed in
the erythrocytes of solely the human species and it displays a genetic
polymorphism. Due to this polymorphism about 25% of the individuals of
the caucasian population lack this activity ("non-conjugators"), while
75% show it ("conjugators") (Hallier, E., et al., 1993). Using our
newly developed HPLC-fluorescence detection assay (Müller, M., et al.,
2001) we have profiled the kinetics of enzyme inhibition in erythrocyte
lysates of two individuals previously identified as "normal conjugator"
(medium enzyme activity) and "super-conjugator" (very high activity).
For the normal conjugator we have determined a 2.77 mM thimerosal
concentration to inhibit 50% of the GST T1 activity. In the case of the
super-conjugator a 2.3 mM thimerosal concentration causes a 50%
inhibition of the enzyme activity. For both phenotypes a 14.8 mM
thimerosal concentration results in residual enzyme activities equal to
those typically detected in non-conjugator lysates. Thus, sufficiently
high doses of thimerosal may be able to change the phenotypic status of
an individual--at least in vitro--by inhibition of the GST T1
enzyme.
16. Determination of bisphenol A concentrations in human biological
fluids reveals significant early prenatal exposure.
Ikezuki Y, Tsutsumi O, Takai Y, Kamei Y, Taketani Y.
Hum Reprod. 2002 Nov;17(11):2839-41.
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.
17. Parent bisphenol A accumulation in the human
maternal-fetal-placental unit.
Schönfelder G, Wittfoht W, Hopp H, Talsness CE, Paul M, Chahoud I.
Environ Health Perspect. 2002 Nov;110(11):A703-7.
http://www.ehponline.org/members/2002/110pA703-A707schonfelder/EHP110pa703PDF.PDF
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.
18. Factors controlling testis descent.
Hughes IA, Acerini CL.
Eur J Endocrinol. 2008 Dec;159 Suppl 1:S75-82.
http://eje-online.org/cgi/content/full/159/suppl_1/S75
Descent of the testis from an intra-abdominal site in foetal life to an
extracorporeal location after birth is a mandatory developmental
process to ensure that the mature testis promotes normal
spermatogenesis. The two phases of transabdominal and inguinoscrotal
descent occur approximately during the first and last thirds of
gestation respectively. Key anatomical events to release the testis
from its urogenital ridge location and to guide the free gonad into the
scrotum are the degeneration of the cranio-suspensory ligament and a
thickening of the gubernaculum. Androgens play a role in both these
processes, particularly with respect to enabling the testis to traverse
the inguinal canal in the final phase of descent. Experiments in
animals suggest that androgens mediate this effect via the release of
calcitonin gene-related peptide by the genitofemoral nerve, but direct
evidence for such a mechanism is lacking in humans. The transabdominal
phase of descent is under the control of insulin-like 3 (INSL3), a
product of the Leydig cells. Definitive evidence of its role in rodent
testis descent is illustrated by the phenotype of bilateral
cryptorchidism in Insl3-/- null mice. Circulating levels of INSL3 are
higher in boys at puberty, are undetectable in girls and are lower in
boys with undescended testes. A minority also have a mutation either in
the INSL3 gene or affecting its receptor gene, relaxin/insulin-like
family peptide receptor 2 (LGRF8). Other factors that may play a role
in testis descent include the anti-Mullerian hormone and members of the
HOX gene family. Evidence that the prevalence of undescended testis may
be increasing provides a phenotypic readout for the effects of
postulated chemicals in the environment interfering in some way with
the action of factors that control testis descent. Epidemiological
studies point to profound geographical variations in prevalence in
countries such as Denmark and Finland. Associations have been found
with levels of chemicals labelled as endocrine disruptors being higher
in breast milk samples from mothers with cryptorchid boys when compared
with controls. The adverse effects of these compounds (e.g. bisphenol
A) can be replicated in the offspring of dams exposed during pregnancy.
A sensitive marker of an anti-androgen effect of a compound is a
reduction in the anogenital distance, an anthropometric measurement
that is significantly greater in males compared with females. The
observation of an association between the anogenital distance in infant
boys and the level of pesticides in the urine of their mothers in late
gestation indicates that this has the potential to be a useful
surrogate marker of the effects of environmental chemicals on testis
descent in human population studies. The rightful place for the testis
at birth is in the scrotum in order to provide the temperature
differential essential for normal spermatogenesis. Appropriate
screening programmes and early surgical intervention are the
prerequisites to ensure optimal fertility in adulthood and a
considerably lessened risk of testis cancer.
18. Associations between indoor environmental factors and
parental-reported autistic spectrum disorders in children 6–8 years of
age
Malin Larsson et al.
Neurotoxicology, In Press, Corrected Proof, Available online 10
February 2009
http://tinyurl.com/cfmyvd
Potential contributions of environmental chemicals and conditions to
the etiology of Autism Spectrum Disorders are the subject of
considerable current research and speculation. The present paper
describes the results of a study undertaken as part of a larger project
devoted to the connection between properties of the indoor environment
and asthma and allergy in young Swedish children. The larger project,
The Dampness in Buildings and Health (DBH) Study, began in the year
2000 with a questionnaire distributed to parents of all children 1–6
years of age in one Swedish county (DBH-I). A second, follow-up
questionnaire (DBH-III) was distributed in 2005. The original survey
collected information about the child, the family situation, practices
such as smoking, allergic symptoms, type of residence, moisture-related
problems, and type of flooring material, which included polyvinyl
chloride (PVC). The 2005 survey, based on the same children, now 6–8
years of age, also asked if, during the intervening period, the child
had been diagnosed with Autism, Asperger's syndrome, or Tourette's
syndrome. From a total of 4779 eligible children, 72 (60 boys, 12
girls) were identified with parentally reported autism spectrum
disorder. A random sample of 10 such families confirmed that the
diagnoses had been made by medical professionals, in accordance with
the Swedish system for monitoring children's health. An analysis of the
associations between indoor environmental variables in 2000 as well as
other background factors and the ASD diagnosis indicated five
statistically significant variables: (1) maternal smoking; (2) male
sex; (3) economic problems in the family; (4) condensation on windows,
a proxy for low ventilation rate in the home; (5) PVC flooring,
especially in the parents’ bedroom. In addition, airway symptoms of
wheezing and physician-diagnosed asthma in the baseline investigation
(2000) were associated with ASD 5 years later. Results from the second
phase of the DBH-study (DBH-II) indicate PVC flooring to be one
important source of airborne phthalates indoors, and that asthma and
allergy prevalence are associated with phthalate concentrations in
settled dust in the children's bedroom. Because these associations are
among the few linking ASD with environmental variables, they warrant
further and more extensive exploration.
19. Associations among hypospadias, cryptorchidism, anogenital
distance, and endocrine disruption.
Hsieh MH, Breyer BN, Eisenberg ML, Baskin LS.
Curr Urol Rep. 2008 Mar;9(2):137-42.
Endocrine disruptors, such as environmental compounds with
endocrine-altering properties, may cause hypospadias and cryptorchidism
in several species, including humans. Anogenital distance is sexually
dimorphic in many mammals, with males having longer anogenital distance
on average than females. Animal models of proposed endocrine disruptors
have associated prenatal exposure with hypospadias, cryptorchidism, and
reduced anogenital distance. Human studies have correlated shorter
anogenital distance to in utero exposure to putative endocrine
disruptors. We review preliminary data suggesting that anogenital
distance is reduced in boys with hypospadia and cryptorchidism. Hence,
human hypospadias and cryptorchidism may be associated with reduced
anogenital distance as a result of endocrine disruption.
20. Prenatal
phthalate exposure is associated with childhood behavior and executive
functioning
Engel SM, Miodovnik A, Canfield RL, Zhu C, Silva MJ, Calafat AM,
Wolff MS.
Environ Health Perspect. 2010 Apr;118(4):565-71. Epub 2010 Jan 8
21. Prenatal
Exposure to Airborne Polycyclic Aromatic Hydrocarbons and Children's
Intelligence at Age 5 in a Prospective Cohort Study in Poland
Edwards SC, Jedrychowski W, Butscher M, Camann D, Kieltyka A, Mroz
E, Flak E, Li Z, Wang S, Rauh V, Perera F.
Environ Health Perspect. 2010 Apr 14. [Epub ahead of print]
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