3. Parallels between attention deficit hyperactivity disorder and
behavioral deficits produced by neurotoxic exposure in monkeys
Environ Health Perspect. 2000 Jun;108 Suppl 3:405-8.
Attention deficit hyperactivity disorder (ADHD) is a disability
that affects between 3 and 7% of children, with a significant number of
individuals continuing to be affected into adolescence and adulthood.
ADHD is characterized in part by an inability to organize complex
sequences of behavior, to persist in the face of distracting stimuli,
and to respond appropriately to the consequences of past behavior.
There are some parallels between the features of ADHD and the behavior
of monkeys exposed developmentally to lead or polychlorinated biphenyls
(PCBs), as evidenced by research from our laboratory. Both lead and PCB
exposure produce deficits on discrimination reversal and spatial
delayed alternation performance; treated monkeys exhibit deficits in
their ability to change an already established response strategy and
inhibit inappropriate responses. Monkeys exposed developmentally to
lead or PCBs also perform differently from control monkeys on a fixed
interval schedule of reinforcement, which requires the temporal
organization of behavior using only internal cues. Whereas the etiology
of ADHD is multifactorial, the possibility that neurotoxic agents in
the environment contribute to the incidence of ADHD warrants attention.
4. Etiologic subtypes of attention-deficit/hyperactivity disorder:
brain imaging, molecular genetic and environmental factors and the
Swanson JM et al.
Neuropsychol Rev. 2007 Mar;17(1):39-59.
Multiple theories of Attention-Deficit/Hyper-activity Disorder
(ADHD) have been proposed, but one that has stood the test of time is
the dopamine deficit theory. We review the narrow literature from
recent brain imaging and molecular genetic studies that has improved
our understanding of the role of dopamine in manifestation of symptoms
of ADHD, performance deficits on neuropsychological tasks, and response
to stimulant medication that constitutes the most common treatment of
this disorder. First, we consider evidence of the presence of dopamine
deficits based on the recent literature that (1) confirms abnormalities
in dopamine-modulated frontal-striatal circuits, reflected by size
(smaller-than-average components) and function (hypoactivation); (2)
clarifies the agonist effects of stimulant medication on dopaminergic
mechanisms at the synaptic and circuit level of analysis; and (3)
challenges the most-widely accepted ADHD-related neural abnormality in
the dopamine system (higher-than-normal dopamine transporter [DAT]
density). Second, we discuss possible genetic etiologies of dopamine
deficits based on recent molecular genetic literature, including (1)
multiple replications that confirm the association of ADHD with
candidate genes related to the dopamine receptor D4 (DRD4) and the DAT;
(2) replication of differences in performance of neuropsychological
tasks as a function of the DRD4 genotype; and (3) multiple genome-wide
linkage scans that demonstrate the limitations of this method when
applied to complex disorders but implicate additional genes that may
contribute to the genetic basis of ADHD. Third, we review possible
environmental etiologies of dopamine deficits based on recent studies
of (1) toxic substances that may affect the dopamine system in early
development and contribute substantially to the etiology of ADHD; (2)
fetal adaptations in dopamine systems in response to stress that may
alter early development with lasting effects, as proposed by the
developmental origins of health and disease hypothesis; and (3)
gene-environment interactions that may moderate selective damage or
adaptation of dopamine neurons. Based on these reviews, we identify
critical issues about etiologic subtypes of ADHD that may involve
dopamine, discuss methods that could be used to address these issues,
and review old and new theories that may direct research in this area
in the future.
5. Gene-environment interplay in attention-deficit hyperactivity disorder
and the importance of a developmental perspective
Thapar A, Langley K, Asherson P, Gill M.
Br J Psychiatry. 2007 Jan;190:1-3.
Attention-deficit hyperactivity disorder (ADHD) varies in its clinical
presentation and course. Susceptibility gene variants for ADHD and
associated antisocial behaviour are being identified with emerging
evidence of gene-environment interaction. Genes and environmental
factors that influence the origins of disorder are not necessarily the
same as those that contribute to its course and outcome.
6. Genetics of Attention Deficit/Hyperactivity Disorder
Wallis D, Russell HF, Muenke M.
J Pediatr Psychol. 2008 Jun 3. [Epub ahead of print]
OBJECTIVE: The intent of this review is to provide an overview for
the practicing psychologist/psychiatrist regarding the complexities of
and the most recent advances made in the study of the genetic basis of
attention-deficit/hyperactivity disorder (ADHD). METHODS: We review a
variety of concepts including: (a) complexities involved in studying
the genetics of ADHD, (b) evidence for a primarily genetic component of
ADHD, (c) evidence suggesting that there are only a few genes with
major effects contributing to ADHD, (d) identification of the best
candidate genes, (e) linkage analysis for the identification of novel
candidate genes, and (f) data on gene-environment interactions.
RESULTS: It is now generally accepted that ADHD has a biological and
even primarily genetic basis. However, despite the identification of
several candidate genes, none of them seems to have a substantial
effect and the exact etiology underlying ADHD has remained elusive.
Genome-wide linkage analysis can help in the identification of novel
candidate genes. While several independent groups have initiated these
studies, we await further details and specific genes from fine-mapping
studies. Most recently, researchers have been trying to identify gene
by environment interactions to help understand ADHD. Replication of
positive findings will be essential in teasing out these combinatorial
influences. CONCLUSIONS: Ideally, one day specific genes with major
effects and specific risk factors with which they interact will be
identified and we will be able to implement personalized medicine.
Knowledge of such genes will allow us to identify specific diagnostic
biological markers. In addition, defining the target genes is the first
step in developing novel drug therapies to treat the ADHD symptoms that
lead to impairment. Furthermore, such markers could also identify at
risk individuals at a younger age in order to implement treatments
sooner to decrease the severity of ADHD symptoms or even to prevent
future ADHD symptomatology.
7. A genetic etiology of pervasive developmental disorder guides
Solomon M, Hessl D, Chiu S, Hagerman R, Hendren R.
Am J Psychiatry. 2007 Apr;164(4):575-80.
8. Dopamine: the rewarding years
Br J Pharmacol. 2006 Jan;147 Suppl 1:S136-44.
Dopamine has moved from being an insignificant intermediary in the
formation of noradrenaline in 1957 to its present-day position as a
major neurotransmitter in the brain. This neurotransmitter is involved
in the control of movement and Parkinson's disease, the neurobiology
and symptoms of schizophrenia and attention deficit hyperactivity
disorder. It is also considered an essential element in the brain
reward system and in the action of many drugs of abuse. This evolution
reflects the ability of several famous names in neuropharmacology,
neurology and psychiatry to apply new techniques to ask and answer the
right questions. There is now excellent knowledge about the metabolism
of dopamine, dopamine receptor systems and the structural organisation
of dopamine pathways in the brain. Less is known about the function of
the different receptors and how the various dopamine pathways are
organised to produce normal behaviour, which exhibits disruption in the
disease states mentioned. In particular, we have very limited
information as to why and how the dopamine system dies or becomes
abnormal in Parkinson's disease or a neurodevelopmental disorder such
as schizophrenia. Dopamine neurones account for less than 1% of the
total neuronal population of the brain, but have a profound effect on
function. The future challenge is to understand how dopamine is
involved in the integration of information to produce a relevant
response rather than to study dopamine in isolation from other
transmission systems. This integrated approach should lead to greater
understanding and improved treatment of diseases involving dopamine.
9. A common haplotype of the dopamine transporter gene associated with
attention-deficit/hyperactivity disorder and interacting with maternal
use of alcohol during pregnancy
Brookes KJ et al.
Arch Gen Psychiatry. 2006 Jan;63(1):74-81.
CONTEXT: Attention-deficit/hyperactivity disorder (ADHD) is a common
heritable childhood behavioral disorder. Identifying risk factors for
ADHD may lead to improved intervention and prevention. The dopamine
transporter gene (DAT1) is associated with ADHD in several studies,
with an average 1.2 odds ratio and evidence of heterogeneity across
data sets. OBJECTIVE: To investigate sources of heterogeneity by
refining the DAT1 association using additional markers and
investigating gene-environment interaction between DAT1 and maternal
use of alcohol and tobacco during pregnancy. DESIGN: Prospective study.
SETTING AND PATIENTS: Children with ADHD from child behavior clinics in
the southeast of England and in the Taipei area of Taiwan.
INTERVENTIONS: Within-family tests of association using 2 repeat
polymorphisms in the 3' untranslated region and intron 8 plus
additional markers in the English sample. MAIN OUTCOME MEASURES:
Transmission ratios of risk alleles from heterozygote parents to
affected offspring and comparison of the transmission ratios in high-
and low-exposure groups for the environmental variables. RESULTS: A
novel association was identified between ADHD, the intron 8
polymorphism, and a specific risk haplotype in both English and
Taiwanese samples. The risk haplotype showed significant interactions
with maternal use of alcohol during pregnancy. CONCLUSIONS: The
identification of a common haplotype in 2 independent populations is an
important step toward identifying functionally significant regions of
DAT1. Interaction between DAT1 genotypes and maternal use of alcohol
during pregnancy suggests that DAT1 moderates the environmental risk
and has implications for the prevention of ADHD. Further studies are
required to delineate the precise causal risk factor involved in this
10. Neurogenetic interactions and aberrant behavioral co-morbidity of
attention deficit hyperactivity disorder (ADHD): dispelling myths
Comings DE, Chen TJ, Blum K, Mengucci JF, Blum SH, Meshkin B.
Theor Biol Med Model. 2005 Dec 23;2:50.
BACKGROUND: Attention Deficit Hyperactivity Disorder, commonly referred
to as ADHD, is a common, complex, predominately genetic but highly
treatable disorder, which in its more severe form has such a profound
effect on brain function that every aspect of the life of an affected
individual may be permanently compromised. Despite the broad base of
scientific investigation over the past 50 years supporting this
statement, there are still many misconceptions about ADHD. These
include believing the disorder does not exist, that all children have
symptoms of ADHD, that if it does exist it is grossly over-diagnosed
and over-treated, and that the treatment is dangerous and leads to a
propensity to drug addiction. Since most misconceptions contain
elements of truth, where does the reality lie? RESULTS: We have
reviewed the literature to evaluate some of the claims and
counter-claims. The evidence suggests that ADHD is primarily a
polygenic disorder involving at least 50 genes, including those
encoding enzymes of neurotransmitter metabolism, neurotransmitter
transporters and receptors. Because of its polygenic nature, ADHD is
often accompanied by other behavioral abnormalities. It is present in
adults as well as children, but in itself it does not necessarily
impair function in adult life; associated disorders, however, may do
so. A range of treatment options is reviewed and the mechanisms
responsible for the efficacy of standard drug treatments are
considered. CONCLUSION: The genes so far implicated in ADHD account for
only part of the total picture. Identification of the remaining genes
and characterization of their interactions is likely to establish ADHD
firmly as a biological disorder and to lead to better methods of
diagnosis and treatment.
11. Smoking during pregnancy and the risk for hyperkinetic disorder in
Linnet KM et al.
Pediatrics. 2005 Aug;116(2):462-7.
OBJECTIVE: Maternal smoking during pregnancy may increase the risk
for behavioral disorders. The aim of this study was to investigate the
association between smoking during pregnancy and hyperkinetic and
attention-deficit/hyperactivity disorder in the offspring in a large
population-based study. METHODS: This study was designed as a nested
case-control study. Data were obtained from Danish longitudinal
registers and included 170 children with hyperkinetic disorder and 3765
population-based control subjects, who were matched by age, gender, and
date of birth. Potential confounders, including newborn
characteristics, socioeconomic status, and family history of
psychiatric illnesses, were evaluated by conditional logistic
regression analyses. RESULTS: Women who smoked during pregnancy had a
3-fold increased risk for having offspring with hyperkinetic disorder
compared with nonsmokers. Socioeconomic factors and history of mental
disorder in the parents or siblings seemed to confound the result to
some extent (adjusted relative risk: 1.9; 95% confidence interval:
1.3-2.8). Adjustment for parental age or exclusion of children with low
birth weight (<2500 g), preterm delivery (<37 weeks completed
gestation), and Apgar scores <7 at 5 minutes revealed no changes in
the results. Also, excluding children with conduct disorders or
comorbid disorders revealed no change in the results. CONCLUSIONS: Our
results showed an increased risk for hyperkinetic disorder in children
of mothers who smoked during pregnancy. This could not be explained by
newborn characteristics, parental socioeconomic status, family history
of psychiatric hospitalizations or contact as outpatients, conduct
disorders, or comorbidity.
12. Relationship between antisocial behaviour, attention-deficit
hyperactivity disorder and maternal prenatal smoking
Button TM, Thapar A, McGuffin P.
Br J Psychiatry. 2005 Aug;187:155-60.
BACKGROUND: There is substantial evidence that maternal smoking
during pregnancy is associated with both antisocial behaviour and
symptoms of attention-deficit hyperactivity disorder (ADHD) in
offspring. However, it is not clear whether maternal smoking during
pregnancy is independently associated with antisocial behaviour or
whether the association arises because antisocial behaviour and ADHD
covary. AIMS: To examine the relationship between maternal smoking
during pregnancy, antisocial behaviour and ADHD in offspring. METHOD:
Questionnaires concerning behaviour and environmental factors were sent
to twins from the CaStANET study and data analysed using a number of
bivariate structural equation models. RESULTS: Maternal prenatal
smoking contributed small but significant amounts to the variance of
ADHD and of antisocial behaviour. The best fitting bivariate model was
one in which maternal prenatal smoking had a specific influence on each
phenotype, independent of the effect on the other phenotype.
CONCLUSIONS: Both antisocial behaviour and ADHD symptoms in offspring
are independently influenced by maternal prenatal smoking during
13. Perinatal complications in children with attention-deficit
hyperactivity disorder and their unaffected siblings
Ben Amor L et al.
Department of Psychiatry, Laval University, Québec.
J Psychiatry Neurosci. 2005 Mar;30(2):120-6.
OBJECTIVES: Genetic and nonshared environmental factors
(experienced by 1 family member to the exclusion of the others) have
been strongly implicated in the causes of attention-deficit
hyperactivity disorder (ADHD). Pregnancy, labour/delivery and neonatal
complications (PLDNC) have often been associated with ADHD; however, no
investigations aimed at delineating the shared or nonshared nature of
these factors have been reported. We aimed to identify those elements
of the PLDNC that are more likely to be of a nonshared nature. METHODS:
We used an intrafamily study design, comparing the history of PLDNC
between children diagnosed with ADHD, according to the criteria of the
Diagnostic and Statistical Manual of Mental Disorders, fourth edition
(DSM-IV), and their unaffected siblings. Children with ADHD were
recruited from the outpatient, day-treatment program of the Child
Psychiatry Department, Douglas Hospital, Montreal. The unaffected
sibling closest in age to the child with ADHD was used as a control.
The history of PLDNC was assessed using the Kinney Medical and
Gynecological Questionnaire and the McNeil-Sjostrom Scale for both
children with ADHD and their siblings. Seventy children with ADHD along
with 50 of their unaffected siblings agreed to participate in the
study. Child Behavior Checklist (CBCL), Continuous Performance Test
(CPT) and Restricted Academic Situation Scale (RASS) scores were also
used as measures of ADHD symptoms in children with ADHD. RESULTS: The
children with ADHD had significantly higher rates of neonatal
complications compared with their unaffected siblings (F4,196 = 3.67, p
< 0.006). Furthermore, neonatal complications in the children with
ADHD were associated with worse CBCL total and externalizing scores and
with poorer performance on the CPT. CONCLUSIONS: These results suggest
that neonatal complications are probably a nonshared environmental risk
factor that may be pathogenic in children with ADHD.
14. Prenatal exposure to polychlorinated biphenyls and attention at school age
Jacobson JL, Jacobson SW.
J Pediatr. 2003 Dec;143(6):780-8.
OBJECTIVE: To examine the relation of prenatal polychlorinated biphenyl
(PCB) exposure to child performance on neuropsychological tests of
attention and information processing.Study design In this prospective,
longitudinal study, assessment of prenatal PCB exposure was based on
umbilical cord serum and maternal serum and milk concentrations. The
children were tested in their homes at age 11 years. Multiple
regression was used to examine the relation of this exposure to
performance on 15 neuropsychological tests after controlling for a
broad range of potential confounding variables. RESULTS: Adverse
effects were seen primarily in children who had not been breast fed. Among these children, prenatal PCB exposure was associated with greater
impulsivity, poorer concentration, and poorer verbal, pictorial, and
auditory working memory. There was no evidence of visual-spatial
deficit or increased hyperactivity. CONCLUSIONS: These findings are
consistent with earlier reports of greater vulnerability to prenatal
PCB exposure in children who were not breast fed. It is not clear
whether the protection offered by breast-feeding is caused by nutrients
in breast milk or better quality of intellectual stimulation often
provided by breast-feeding mothers.
15. Intellectual impairment in children exposed to polychlorinated biphenyls in utero
Jacobson JL, Jacobson SW.
N Engl J Med. 1996 Sep 12;335(11):783-9.
BACKGROUND: In utero exposure to polychlorinated biphenyls, a
ubiquitous environmental contaminant, has been linked to adverse
effects on neurologic and intellectual function in infants and young
children. We assessed whether these effects persist through school age
and examined their importance in the acquisition of reading and
arithmetic skills. METHODS: We tested 212 children, recruited as
newborns to overrepresent infants born to women who had eaten Lake
Michigan fish contaminated with polychlorinated biphenyls. A battery of
IQ and achievement tests was administered when the children were 11
years of age. Concentrations of polychlorinated biphenyls in maternal
serum and milk at delivery were slightly higher than in the general
population. A composite measure of prenatal exposure was derived from
concentrations in umbilical-cord serum and maternal serum and milk.
RESULTS: Prenatal exposure to polychlorinated biphenyls was associated
with lower full-scale and verbal IQ scores after control for potential
confounding variables such as socioeconomic status (P = 0.02). The
strongest effects related to memory and attention. The
most highly exposed children were three times as likely to have low
average IQ scores (P <0.001) and twice as likely to be at least two
years behind in reading comprehension (P = 0.03). Although
larger quantities of polychlorinated biphenyls are transferred by
breast-feeding than in utero, there were deficits only in associated
with transplacental exposure, suggesting that the developing fetal
brain is particularly sensitive to these compounds. CONCLUSIONS: In
utero exposure to polychlorinated biphenyls in concentrations slightly
higher than those in the general population can have a long-term impact
on intellectual function.
16. Effects of environmental exposure to polychlorinated biphenyls and
dioxins on cognitive abilities in Dutch children at 42 months of age
Patandin S et al.
J Pediatr. 1999 Jan;134(1):33-41.
OBJECTIVE: To study possible adverse effects of environmental exposure
to polychlorinated biphenyls (PCB) and dioxins on cognitive functioning
in young children. METHODS: In a follow-up of the Dutch PCB/Dioxin
study, cognitive abilities were assessed with the Kaufman Assessment
Battery for Children in 42-month-old children (n = 395). In a subgroup
(n = 193) verbal comprehension was assessed with the Reynell Language
Developmental Scales. Prenatal PCB exposure was estimated from the sum
of PCBs 118, 138, 153, and 180 (SigmaPCB) in maternal plasma.
Lactational exposure was assessed from breast milk PCB and dioxin
concentrations, multiplied by the number of weeks of breast-feeding.
Current PCB body burden was estimated from SigmaPCB in 42-month-old
plasma samples. RESULTS: After adjustment was done for covariables,
maternal SigmaPCB was associated with lower scores on the overall
cognitive and sequential and simultaneous processing scales of the
Kaufman Assessment Battery for Children (all P <.05). The highest
exposed group (SigmaPCB >/= 3 microg/L) scored 4 points lower on all
3 scales of the K-ABC when compared with the lowest exposed group
(SigmaPCB < 1.5 microg/L). Both lactational exposure and current
exposure to PCBs and dioxins were not related to 42-month cognitive
performance. CONCLUSIONS: In utero exposure to "background" PCB
concentrations is associated with poorer cognitive functioning in
preschool children. Children of mothers at the upper end of exposure
are especially at risk. Therefore maternal PCB body burden should be
reduced, and breast-feeding should not be discouraged.
17. Environmental exposure to polychlorinated biphenyls (PCBs) and dioxins.
Consequences for longterm neurological and cognitive development of the
Boersma ER, Lanting CI.
Adv Exp Med Biol. 2000;478:271-87.
Polychlorinated biphenyls (PCBs) and dioxins are environmental
pollutants. Prenatally, as well as postnatally through breast feeding,
large amounts are transferred from mother to the child. Formula is free
of these substances. Considering their potential developmental
neurotoxicity, we investigated long term effects of perinatal exposure
to PCBs and dioxins on neurological and cognitive development. Given
the evidence that PCBs exert oestrogenic effects, and oestrogens are
known to suppress lactation, we investigated the effect of maternal PCB
body load on lactation performances as well. METHODS: A group of 418
infants were followed from birth up to 6 years of age. Half of them
were fully breast fed (BF) for at least 6 weeks. Prenatal PCB exposure
was measured from cord and maternal blood. Postnatal exposure was
reflected by PCB and dioxin levels in breast and formula milk and
plasma PCB levels at 42 months of age. Both neurological and cognitive
development were taken as outcome variable at 18, 42 months and at 6
years of age. At 18 and 42 months of age neurological condition was
evaluated according to Hempel and at 6 years of age according to
Touwen. Condition was evaluated in terms of optimality. Separately, the
fluency of movements was scored. Cognitive abilities were measured at
18 months by the Bayley Scales of Infant Development, at 42 months of
age by the Kaufman Assessment Battery for Children (K-ABC) and at 6
years of age by the McCarthy Scales. Daily breast milk volume and milk
fat content in relation to PCB body load was evaluated in 102 mothers.
Multivariate regression models were applied to analyse associations of
measured exposure variables with independent variables adjusted for
confounders. RESULTS: At 18 months of age cognitive development was not
affected by either pre- or postnatal exposure to the measured PCBs and
dioxins. However, neurological examination showed an adverse effect of
prenatal exposure to the measured pollutants on neurological optimality
score. At 42 months of age we found negative associations between
prenatal PCB exposure on cognitive development. However no effect was
demonstrated on postnatal exposure to the measured pollutants.
Neurological development was not affected by either pre- or postnatal
exposure to PCBs and dioxins. At 6 years of age the preliminary results
revealed evidence that cognitive development is affected by prenatal
exposure to these pollutants in children from young mothers. An adverse
effect of prenatal exposure on neurological outcome was also
demonstrated in the formula fed group but not in the breast fed group.
Despite a higher PCB exposures from breast milk we found at 18 months,
42 months of age, and at 6 years of age a beneficial effect of breast
feeding on the quality of movements, in terms of fluency, and on the
cognitive development tests. Maternal PCB body load was inversely
related to 24-h breast milk volume and milk fat content. CONCLUSION: These data give evidence that prenatal exposure to PCBs do have subtle
negative effects on neurological and cognitive development of the child
up to school-age. Human breast milk volume and fat content is adversely
affected by the presently encountered PCB levels in W. Europe. Our
studies showed evidence that breast feeding counteracts the adverse
developmental effects of PCBs and dioxins.
18. Effects of prenatal PCB and dioxin background exposure on cognitive and motor abilities in Dutch children at school age
Vreugdenhil HJ et al.
J Pediatr. 2002 Jan;140(1):48-56.
OBJECTIVE: Our purpose was to evaluate whether effects of exposure to
environmental levels of PCBs and dioxins on development in the Dutch
cohort persist until school age. STUDY DESIGN: In the Dutch PCB/dioxin
study, cognitive and motor abilities were assessed with the McCarthy
Scales of Children's Abilities in children at school age. During
infancy, half of this population was fully breast-fed for at least >
or = 6 weeks and the other half formula fed. Prenatal exposure to PCBs
was defined as the sum of PCB118, 138, 153, and 180 in maternal and
cord plasma. In breast milk, additional measurements of 17 dioxins, 6
dioxin-like PCBs, and 20 nondioxin-like PCBs were done. RESULTS: Negative effects of prenatal PCB and dioxin exposure on cognitive and
motor abilities were seen when parental and home characteristics were
less optimal. These effects were not measurable in children raised in
more optimal environments. CONCLUSIONS: Neurotoxic effects of prenatal
PCB and dioxin exposure may persist into school age, resulting in
subtle cognitive and motor developmental delays. More optimal
intellectual stimulation provided by a more advantageous parental and
home environment may counteract these effects of prenatal exposure to
PCBs and dioxins on cognitive and motor abilities.
19. Human prenatal and postnatal exposure to polybrominated diphenyl
ethers, polychlorinated biphenyls, polychlorobiphenylols, and
Guvenius DM et al.
Environ Health Perspect. 2003 Jul;111(9):1235-41.
The aim of this study was to determine human prenatal and postnatal
exposures to polybrominated diphenyl ethers (PBDEs), polychlorinated
biphenyls (PCBs), hydroxylated metabolites of PCBs
(polychlorobiphenylols; OH-PCBs), and pentachlorophenol (PCP). The
median PBDE fresh-weight concentrations in maternal and cord blood
plasma and in breast milk were 24, 4.3, and 75 pg/g, respectively. The
PCB concentrations were approximately 60 times higher in each
compartment (1,560, 277, and 4,310 pg/g, respectively). Calculated on a
lipid weight basis, the levels were comparable in maternal blood plasma
and breast milk. In contrast to PCBs, differences were found between
PBDE congener distribution in maternal and cord blood plasma. The
OH-PCBs constituted up to 26% of the PCB levels in maternal blood
plasma and 53% in cord blood plasma, with levels of 120 and 88 pg/g
fresh weight, respectively, and in breast milk 3 pg/g. The
corresponding concentrations for PCP were 2,830, 1,960, and 20 pg/g.
The ratios of PCB to OH-PCB were 13, 3, and 1,400 in maternal, cord
plasma, and breast milk, respectively. It is evident that prenatal
exposures occur for all the analytes. Moreover, the exposure continues
after birth via breast milk. However, levels of OH-PCBs and PCP in
breast milk are low compared with levels in blood plasma. Exposures to
both PCBs and PBDEs, and in particular to the endocrine-active
halogenated phenolic compounds, are of concern and implicate a
potential risk for developmental disturbances.
20. 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.
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.
21. Impairments of memory and learning in older adults exposed to polychlorinated biphenyls via consumption of Great Lakes fish
Schantz SL et al.
Environ Health Perspect. 2001 Jun;109(6):605-11.
An association between in utero polychlorinated biphenyl (PCB) exposure
and impaired childhood intellectual functioning has been reported, but
the potential impact of PCB exposure during adulthood on intellectual
functioning has received little attention. We assessed the impact of
PCBs and other fish-borne contaminants on intellectual functioning in
older adults. The subjects were 49- to 86-year-old Michigan residents
recruited from an existing cohort. Fish eaters ate > 24 lb of
sport-caught Lake Michigan fish per year and non-fish eaters ate < 6
lb of Lake Michigan fish per year. A battery of cognitive tests
including tests of memory and learning, executive function, and
visual-spatial function was administered to 180 subjects (101 fish
eaters and 79 non-fish eaters). Blood samples were analyzed for PCBs
and 10 other contaminants. We evaluated cognitive outcomes using
multiple regression. PCBs and dichlorodiphenyl dichloroethene (DDE)
were markedly elevated in fish eaters. After controlling for potential
confounders PCB, but not DDE, exposure was associated with lower scores
on several measures of memory and learning. These included the Weschler
Memory Scale verbal delayed recall (p = 0.001), the semantic cluster
ratio (p = 0.006), and list A, trial 1 (p = 0.037), from the California
Verbal Learning Test. In contrast, executive and visual-spatial
function were not impaired by exposure to either PCBs or DDE. In
conclusion, PCB exposure during adulthood was associated with
impairments in memory and learning, whereas executive and
visual-spatial function were unaffected. These results are consistent
with previous research showing an association between in utero PCB
exposure and impairments of memory during infancy and childhood.
22. Depuration of polybrominated diphenyl ethers (PBDEs) and
polychlorinated biphenyls (PCBs) in breast milk from California
first-time mothers (primiparae)
Hooper K et al.
Environ Health Perspect. 2007 Sep;115(9):1271-5.
BACKGROUND: Little is known about the rates of loss (depuration) of
polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls
(PCBs) from mothers during lactation. Depuration rates affect infant
exposure to chemicals during breast-feeding, and fetal and lactational
transfers during subsequent pregnancies. OBJECTIVE: Our objective in
this study was to estimate depuration rates of PBDEs and PCBs using
serial samples of breast milk. METHOD: Nine first-time mothers
(primiparae) each collected samples at 4, 6, 8, 12, 16, 20, and 24
weeks after birth. Nine additional primiparae each collected two
samples at varying time intervals (18 to > 85 weeks after birth).
Analytical precision was assessed to evaluate the accuracy of measured
monthly percentage declines in PBDEs and PCBs. RESULTS: The four major
PBDE congeners decreased 2 or 3% +/- 1% per month over the 6-month
period. These decreases were consistent over a 50-fold range (21-1,330
ng/g lipid weight) of initial PBDE concentrations in breast milk. The
change in PCB-153 ranged from + 0.3% to -0.6% per month, with
heterogeneous slopes and greater intraindividual variability. PBDE and
PCB concentrations declined 1% per month over longer periods (up to 136
weeks). CONCLUSIONS: Our data indicate that PBDEs and PCBs are not
substantially (4-18%) reduced in primiparae after 6 months of
breast-feeding. Consequently, the fetal and lactational exposures for a
second child may not be markedly lower than those for the first.
Participants were volunteers from a larger study population (n = 82),
and were typical in their PBDE/PCB levels and in many demographic and
lifestyle factors. These similarities suggest that our results may have
23. Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in breast milk from the Pacific Northwest
She J et al.
Chemosphere. 2007 Apr;67(9):S307-17.
Breast milk samples from 40 first-time mothers from the Pacific
Northwest of the US and Canada were analyzed for polybrominated
diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs). Total
PBDEs (summation operator PBDEs), calculated by summing values for the
12 PBDEs congeners analyzed, ranged from 6 to 321 ppb (lipid weight)
(mean=96 ppb; median=50 ppb). In approximately 40% of the women
(15/40), summation operator PBDEs>100 ppb lw in their milk, and four
samples had levels >250 ppb lw. PBDE 47 was the dominant congener in
most samples, whereas PBDE 153 was predominant in a few (3/40).
summation operator PCBs were calculated by summing values for the 82
PCB congeners analyzed, and ranged from 49 to 415 ppb (lipid weight)
(mean=147 ppb; median=126 ppb). approximately 30% of the mothers
(13/40) have summation operator PBDEs> summation operator PCBs in
their milk samples, and approximately 65% (25/40) have BDE 47>PCB
153 in breast milk samples, with BDE 47 averaging 3-fold greater levels
than PCB 153. Clearly, the lower brominated PBDEs are surpassing PCBs
as a major environmental concern in North America, and are likely
affecting significant portions of the populations in these regions.
PBDEs have become a major persistent organic pollutant. However, there
are no positive correlations between levels of summation operator PBDEs
and summation operator PCBs, or between levels of PBDE 47 and PCB 153,
suggesting there may be some differences in exposure pathways for PBDEs
and PCBs in humans.
24. Distribution of PCDDs/PCDFs and Co-PCBs in human maternal blood, cord
blood, placenta, milk, and adipose tissue: dioxins showing high toxic
equivalency factor accumulate in the placenta
Suzuki G, Nakano M, Nakano S.
Biosci Biotechnol Biochem. 2005 Oct;69(10):1836-47.
To assess levels of dioxin background contamination and transfer of
dioxins from mothers to unborn children and infants, concentrations of
polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated
dibenzofurans (PCDFs), and coplanar-polychlorinated biphenyls (Co-PCBs)
were measured in human samples from expectant and nursing mothers
living in Nara, Japan. The average toxic equivalency quantities (TEQs)
of PCDDs/PCDFs and Co-PCBs from circulating maternal blood, cord blood,
placenta, milk taken 3-10 d after delivery, milk taken one month after
delivery, and adipose tissue were 26 and 9.3, 15 and 2.3, 31 and 1.2,
16 and 5.4, 18 and 8.8, and 16 and 7.7 pg-TEQ/g-fat, respectively.
Among the various PCDD/PCDF congeners, 1,2,3,7,8-PeCDD and
2,3,4,7,8-PeCDF contributed most heavily to the TEQs of all maternal
samples. Among the various Co-PCB congeners, 3,3',4,4',5-PeCB (#126),
2,3,3',4,4',5-HxCB (#156), and 2,3',4,4',5-PeCB (#118) contributed most
heavily to the TEQs of all maternal samples. But, the concentrations
and relative percentages of congeners differed among the various
samples, suggesting that congeners showing high toxic equivalency
factor accumulate in the placenta.
25. Distribution of PCBs and organochlorine pesticides in umbilical cord and maternal serum
Covaci A, Jorens P, Jacquemyn Y, Schepens P.
Sci Total Environ. 2002 Oct 21;298(1-3):45-53.
Polychlorinated biphenyls (PCBs) and organochlorine pesticides, such as
hexachlorobenzene (HCB) and
1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethylene (p,p'-DDE) are
compounds widespread in the environment, highly lipophilic, and
accumulate in biological systems. The newborn are exposed to these
organochlorine compounds across the placenta and through breastfeeding.
This study reports the levels of selected PCB congeners, p,p'-DDE and
HCB in maternal blood and cord blood samples collected at delivery
between November and December 1999 from 44 women living in the urban
area of Antwerp, Belgium. Results show that all newborns contained
detectable levels of PCBs, p,p'-DDE and HCB. The median concentration
of PCBs was 450 pg/ml and ranged between 120 and 1580 pg/ml, while the
median concentrations of HCB and p,p'-DDE were 70 and 490 pg/ml,
respectively. Concentrations of PCBs and p,p'-DDE in cord blood (ng/ml)
were positively associated with concentrations in maternal blood
(ng/ml) (coefficients=0.74 and 0.92, P<0.05). We conclude that all
investigated organochlorine compounds have an efficient transplacental
26. Pentachlorophenol and hydroxylated polychlorinated biphenyl metabolites
in umbilical cord plasma of neonates from coastal populations in Québec
Sandau CD, Ayotte P, Dewailly E, Duffe J, Norstrom RJ.
Environ Health Perspect. 2002 Apr;110(4):411-7.
Concentrations of polychlorinated biphenyls (PCBs), hydroxylated
metabolites of PCBs (HO-PCBs) and octachlorostyrene (4-HO-HpCS), and
pentachlorophenol (PCP) were determined in umbilical cord plasma
samples from three different regions of Québec. The regions studied
included two coastal areas where exposure to PCBs is high because of
marine-food-based diets--Nunavik (Inuit people) and the Lower North
Shore of the Gulf of St. Lawrence (subsistence fishermen)--and a
southern Québec urban center where PCB exposure is at background levels
(Québec City). The main chlorinated phenolic compound in all regions
was PCP. Concentrations of PCP were not significantly different among
regions (geometric mean concentration 1,670 pg/g, range 628-7,680 pg/g
wet weight in plasma). The ratio of PCP to polychlorinated biphenyl
congener number 153 (CB153) concentration ranged from 0.72 to 42.3. Sum
HO-PCB (sigma HO-PCBs) concentrations were different among regions,
with geometric mean concentrations of 553 (range 238-1,750), 286
(103-788), and 234 (147-464) pg/g wet weight plasma for the Lower North
Shore, Nunavik, and the southern Québec groups, respectively. Lower
North Shore samples also had the highest geometric mean concentration
of sum PCBs (sum of 49 congeners; sigma PCBs), 2,710 (525-7,720) pg/g
wet weight plasma. sigma PCB concentrations for Nunavik samples and
southern samples were 1,510 (309-6,230) and 843 (290-1,650) pg/g wet
weight plasma. Concentrations (log transformed) of sigma HO-PCBs and
sigma PCBs were significantly correlated (r = 0.62, p < 0.001), as
were concentrations of all major individual HO-PCB congeners and
individual PCB congeners. In Nunavik and Lower North Shore samples,
free thyroxine (T4) concentrations (log transformed) were negatively
correlated with the sum of quantitated chlorinated phenolic compounds
(sum PCP and sigma HO-PCBs; r = -0.47, p = 0.01, n = 20) and were not
correlated with any PCB congeners or sigma PCBs. This suggests that PCP
and HO-PCBs are possibly altering thyroid hormone status in newborns,
which could lead to neurodevelopmental effects in infants. Further
studies are needed to examine the effects of chlorinated phenolic
compounds on thyroid hormone status in newborns.
27. Dietary exposure to polychlorinated biphenyls and dioxins from infancy
until adulthood: A comparison between breast-feeding, toddler, and
Patandin S et al.
Environ Health Perspect. 1999 Jan;107(1):45-51.
Food is the major source for polychlorinated biphenyl (PCB) and dioxin
accumulation in the human body. Therefore, investigating food habits
from early ages until reproductive age (25 years) is important in order
to assess exposure risk for the next generation. The objective of this
study was to assess the PCB/dioxin exposure and the relative
contribution of different foods to total exposure during preschool age.
Particularly, the importance of lactational PCB/dioxin exposure vs.
dietary exposure until adulthood was investigated. A cohort of 207
children was studied from birth until preschool age. Based on 3 planar
PCBs and 17 2,3,7,8-substituted dibenzo-para-dioxins (PCDDs) and
dibenzofurans (PCDFs) measured in breast milk, a model was developed to
calculate the cumulative toxic equivalent (TEQ) intake during
breast-feeding (0-1 year). In 3. 5-year-old children, daily dietary
intake of planar PCB-TEQ and dioxin-TEQ was measured with a validated
food questionnaire. Cumulative TEQ intake from 1 to 5 years was
estimated using the PCB- and dioxin-TEQ intake measured with the food
questionnaire. Cumulative TEQ intake from 6 to 25 years was estimated
using national food consumption and contamination data of PCB- and
dioxin-TEQ intake. In toddlers, dairy products contributed 43% to
PCB-TEQ and 50% to dioxin-TEQ intake. Meat and meat products
contributed 14% and 19%, respectively, and processed foods 23% and 15%,
respectively. Breast-feeding for 6 months contributed to the cumulative
PCB/dioxin TEQ intake until 25 years of age, 12% in boys and 14% in
girls. The daily TEQ intake per kilogram body weight is 50 times higher
in breast-fed infants and three times higher in toddlers than in
adults. Long-term dietary exposure to PCBs and dioxins in men and women
is partly due to breast-feeding (12 and 14%, respectively). After
weaning, dairy products, processed foods, and meat are major
contributors of PCB and dioxin accumulation until reproductive age.
Instead of discouraging breast-feeding, maternal transfer of PCBs and
dioxins to the next generation must be avoided by enforcement of strict
regulations for PCB and dioxin discharge and by reducing consumption of
animal products and processed foods in all ages.
28. Time course of PCDD/PCDF/PCB concentrations in breast-feeding mothers and their infants
Abraham K et al.
Chemosphere. 1998 Oct-Nov;37(9-12):1731-41.
PCDD/PCDF/PCB concentrations were measured in samples from four mothers
(at delivery and during lactation) and their infants (at birth and the
end of first year of life). For two of these mothers it was the second
delivery and breast-feeding period, and additional data were available
from first lactation period and the first-born infant at the age of 11
to 12 months. Five of the six infants were fully breast-fed for at
least 17 weeks. In four of them a distinct PCDD/PCDF/PCB accumulation
was observed at the end of the first year of life: concentrations in
blood fat were 1.5 to 3.6 times higher than maternal levels measured at
the same time. Due to decreasing maternal body burdens during
lactation, PCDD/PCDF concentrations at 11 to 12 months of life were
only about half as high in the second infant as in the first one at the
same age. During second pregnancy, no important change of the
concentrations was observed in maternal blood.
29. Plasma polychlorinated biphenyl levels in Dutch preschool children either breast-fed or formula-fed during infancy
Patandin S et al.
Am J Public Health. 1997 Oct;87(10):1711-4.
OBJECTIVES: This study examined the influence of lactational and in
utero exposure to polychlorinated biphenyls (PCBs) on plasma PCB levels
in children. METHODS: Plasma PCB levels were measured in 173 children
at 3.5 years, of whom 91 were breast-fed and 82 were formula-fed in
infancy. RESULTS: Median plasma PCB levels were 3.6 times higher in
breast-fed children (0.75 microgram/L) than in their formula-fed peers
(0.21 microgram/L). Breast-feeding period and breast-milk PCB levels
were important predictors for PCB levels in the breast-fed group. For
children in the formula-fed group, PCB levels were significantly
related to their material plasma PCB levels. CONCLUSIONS: PCB levels in
Dutch preschool children are related to transfer of maternal PCBs;
therefore, strategies should be aimed at reducing maternal PCB body
30. Toxic threats to neurologic development of children
Environ Health Perspect. 2001 Dec;109 Suppl 6:813-6.
Learning disabilities, attention deficit hyperactivity disorder,
developmental delays, and emotional and behavioral problems are among
childhood disabilities of increasing concern. Interacting genetic,
environmental, and social factors are important determinants of
childhood brain development and function. For many reasons, however,
studying neurodevelopmental vulnerabilities in children is challenging.
Moreover, inadequate incidence and trend data interfere with full
understanding of the magnitude of the problem. Despite these
difficulties, extensive laboratory and clinical studies of several
neurodevelopmental toxicants, including lead, mercury, polychlorinated
biphenyls, alcohol, and nicotine, demonstrate the unique vulnerability
of the developing brain to environmental agents at exposure levels that
have no lasting effect in adults. Historically, understanding the
effects of these toxicants on the developing brain has emerged slowly
while generations of children are exposed to unsafe levels.
Unfortunately, with few exceptions, neurodevelopmental toxicity data
are missing for most industrial chemicals in widespread use, even when
populationwide exposures are documented. The personal, family, and
communitywide costs of developmental disabilities are profound. In
addition to the need for more research, a preventive public health
response requires mitigation of exposures to potential
neurodevelopmental toxicants when available evidence establishes the
plausibility of harm, despite residual toxicologic uncertainties.
31. Poisoning young minds
Environ Health Perspect. 1999 Jun;107(6):A302-7.
For some neurotoxic chemicals, neurobehavioral effects are now
considered to be among the most sensitive end points yet detected,
particularly if exposures occur during critical windows of
vulnerability. Chemically induced problems with perception and
cognitive ability in children can be hard to identify; teasing them out
of a host of genetic and sociocultural influences is a difficult task.
Today, most data on environmentally relevant neurobehavioral effects in
children are concentrated in three chemicals: lead, methylmercury, and
polychlorinated biphenyls. But mounting evidence of the neurobehavioral
effects of chemicals along with growing public concern over pediatric
mental health problems such as attention deficit/hyperactivity disorder
dictates that scientists and legislators improve test methods, explore
mechanisms, and develop appropriate strategies for risk assessment and
33. Dopamine transporter genotype influences the physiological response to medication in ADHD
32. Interaction of dopamine transporter genotype with prenatal smoke
exposure on ADHD symptoms
Becker K, El-Faddagh M, Schmidt MH, Esser G, Laucht M.
J Pediatr. 2008 Feb;152(2):263-9. Epub 2007 Oct 24.
OBJECTIVE: To demonstrate that children homozygous for the
10-repeat allele of the common dopamine transporter (DAT1) polymorphism
who were exposed to maternal prenatal smoke exhibited significantly
higher hyperactivity-impulsivity than children without these
environmental or genetic risks. STUDY DESIGN: We performed a
prospective longitudinal study from birth into early adulthood
monitoring the long-term outcome of early risk factors. Maternal
prenatal smoking was determined during a standardized interview with
the mother when the child was 3 months old. At age 15 years, 305
adolescents participated in genotyping for the DAT1 40 base pair
variable number of tandem repeats polymorphism and assessment of
inattention, hyperactivity-impulsivity, and oppositional
defiant/conduct disorder symptoms with the Kiddie-Sads-Present and
Lifetime Version. RESULTS: There was no bivariate association between
DAT1 genotype, prenatal smoke exposure and symptoms of attention
deficit hyperactivity disorder. However, a significant interaction
between DAT1 genotype and prenatal smoke exposure emerged (P = .012),
indicating that males with prenatal smoke exposure who were homozygous
for the DAT1 10r allele had higher hyperactivity-impulsivity than males
from all other groups. In females, no significant main effects of DAT1
genotype or prenatal smoke exposure or interaction effects on any
symptoms were evident (all P > .25). CONCLUSIONS: This study
provides further evidence for the multifactorial nature of attention
deficit hyperactivity disorder and the importance of studying both
genetic and environmental factors and their interaction.
Gilbert DL et al.
Brain. 2006 Aug;129(Pt 8):2038-46.
Attention deficit hyperactivity disorder (ADHD) is a complex,
multifactorial disorder characterized by physical hyperactivity and
behavioural disinhibition. Short interval cortical inhibition (SICI),
measured in motor cortex with transcranial magnetic stimulation, is
reduced in ADHD and correlates with symptom severity. However, ADHD
medication-induced changes in SICI vary widely among normal individuals
and have not been well studied in children with ADHD. Therefore, we
undertook this study to measure and compare effects of two ADHD
medications, methylphenidate (MPH), a psychostimulant, and atomoxetine
(ATX), a selective norepinephrine reuptake inhibitor, on SICI in
children with ADHD. In addition, we wished to determine whether a
genetic variation in the dopamine transporter (DAT1), a site of action
of MPH, could influence the effects of MPH or ATX on SICI. We performed
a randomized, double-blind, single-dose, crossover study comparing 0.5
mg/kg MPH with 1.0 mg/kg ATX in 16 children with ADHD, aged 8-17. Seven
were homozygotes and 9 heterozygotes for the DAT1 variable number of
tandem repeats 10-repeat allele. Medication and genotype effects on
SICI were estimated with repeated measures, mixed model regression. We
found that MPH and ATX had similar effects on SICI. However, medication
effects differed significantly by DAT1 genotype [F(2,13) = 13.04, P =
0.0008]. Both MPH and ATX increased SICI in heterozygotes but not in
10-repeat homozygotes. In conclusion, MPH and ATX have similar effects
on SICI in children with ADHD. A genetic variation in DAT1, previously
linked to ADHD risk and MPH behavioural responses, influences the
neurophysiological effects of both MPH and ATX.
34. Monoamine oxidase A gene polymorphism predicts adolescent outcome of attention-deficit/hyperactivity disorder
Li J et al.
Am J Med Genet B Neuropsychiatr Genet. 2007 Jun 5;144B(4):430-3.
ADHD is generally deemed to be a highly heritable disorder with mean
heritability of 0.75. The enzyme monoamine oxidase (MAO), which has
both A and B types, has long been considered a candidate pathological
substrate for ADHD, and more recently, the genes for both MAO enzymes
have been examined as mediators of the illness. Previous studies
indicated that 30-50% of children with ADHD will experience symptoms
that persist into adolescence and will have more significant impairment
in social and neuropsychological functioning compared to those whose
symptoms have remitted. Genes may also influence these characteristics
of the disorder, and in this context MAO genes may also be candidates
for moderating the presentation of ADHD. The current study examined the
association between adolescent outcome of ADHD and MAO gene
polymorphisms, including the 941T > G polymorphism in exon 8
(rs1799835) and 1460C > T polymorphism in exon 14 (rs1137070) of the
MAOA gene, and the A > G polymorphism in intron13 (rs1799836), C
> T polymorphism in the 3'UTR (rs1040399), and 2327T > C
polymorphism in exon15 of the MAOB gene. Significant associations were
observed between the MAOA gene polymorphisms and ADHD remission. Due to
the small sample size and the possibility of phenotypic and etiologic
heterogeneity of ADHD outcomes across ethnic or geographic groups,
these results must be replicated before they can be generalized to
other populations. (c) 2007 Wiley-Liss, Inc.
35. Twin study of the etiology of comorbidity between reading disability and attention-deficit/hyperactivity disorder
Willcutt EG, Pennington BF, DeFries JC.
Am J Med Genet. 2000 Jun 12;96(3):293-301.
This study utilized a sample of 313 eight- to sixteen-year-old same-sex
twin pairs (183 monozygotic, 130 dizygotic) to assess the etiology of
comorbidity between reading disability (RD) and
attention-deficit/hyperactivity disorder (ADHD). RD was assessed by a
discriminant function score based on the Peabody Individual Achievement
Test, a standardized measure of academic achievement. The DSM-III
version of the Diagnostic Interview for Children and Adolescents was
used to assess symptoms of ADHD, and separate factor scores were
computed for inattention and hyperactivity/impulsivity (hyp/imp).
Individuals with RD were significantly more likely than individuals
without RD to exhibit elevations on both symptom dimensions, but the
difference was larger for inattention than hyp/imp. Behavior genetic
analyses indicated that the bivariate heritability of RD and
inattention was significant (h(2)(g(RD/Inatt)) = 0.39), whereas the
bivariate heritability of RD and hyp/imp was minimal and nonsignificant
(h(2)(g(RD/Hyp)) = 0.05). Approximately 95% of the phenotypic
covariance between RD and symptoms of inattention was attributable to
common genetic influences, whereas only 21% of the phenotypic overlap
between RD and hyp/imp was due to the same genetic factors.
36. Association of the serotonin transporter and 5HT1Dbeta receptor genes
with extreme, persistent and pervasive aggressive behaviour in children
Davidge KM, Atkinson L, Douglas L, Lee V, Shapiro S, Kennedy JL, Beitchman JH.
Psychiatr Genet. 2004 Sep;14(3):143-6.
There is an inverse correlation between central nervous system
serotonergic activity and human aggression, and aggressive traits are
at least partially heritable. The present study sought to investigate
the relationship between childhood aggression and polymorphisms of two
serotonin system genes: the 5HT1Dbeta receptor gene and the serotonin
transporter (5HTT) gene. Fifty children with a minimum 2-year history
of aggression and scores above the 90th percentile on the Aggression
subscales of both the Child Behaviour Checklist and the Teacher's
Report Form were included in the study. All probands and locally
recruited ethnically matched controls were genotyped for the 5HT1Dbeta
G861C, 5HTTLPR (promoter) and 5HTT variable number of tandem repeats
(VNTR) polymorphisms. Chi-square tests revealed a significantly reduced
frequency of the 5HTT VNTR 10R allele in children displaying the
high-aggression phenotype compared with normal controls (P=0.039).
After correction for multiple comparisons, this association reached the
level of a trend but was no longer significant. Probands also
demonstrated an increased 5HT1Dbeta 861C allele frequency, but this was
not statistically significant (P=0.156). 5HTTLPR was not found to be
significantly associated with aggression, but our data support previous
findings of an association between this polymorphism and attention
deficit hyperactivity disorder (P=0.025). While these preliminary
findings should be interpreted cautiously, our data suggest that the
5HTT VNTR polymorphism is associated with measures of aggressive
behaviour in a sample of children displaying extreme, persistent and
37. Serotonin transporter polymorphisms and persistent, pervasive childhood aggression
Beitchman JH, Baldassarra L, Mik H, De Luca V, King N, Bender D, Ehtesham S, Kennedy JL.
Am J Psychiatry. 2006 Jun;163(6):1103-5.
OBJECTIVE: The purpose of this study was to examine the potential
association of the serotonin transporter (5-HTT) gene and childhood
aggression by testing the 5-HTT variable-number-tandem-repeat and
serotonin transporter promoter polymorphism (5-HTTLPR), including the
recently discovered Lg allelic variant of 5-HTTLPR. METHOD: Clinically
referred children displaying extreme aggression, with a minimum 2-year
history, were genotyped for 5-HTTLPR (N=77) and 5-HTT
variable-number-tandem-repeat (N=78). Analyses compared genotype
frequencies of the aggressive children with healthy comparison
subjects. RESULTS: The "low expressing" genotypic variants of the
5-HTTLPR polymorphism (S/S, Lg/S, Lg/Lg) were significantly associated
with childhood aggression. CONCLUSIONS: This is the first study to
report a significant association between the 5-HTTLPR gene and
38. Children with Starving Brains: A Medical Treatment Guide for Autism Spectrum Disorder, 3rd edition 2007.
by Jaquelyn McCandless, M.D.
with contributions by Jack Zimmerman, Ph.D., and Teresa Binstock, Independent Researcher with Asperger's Disorder.
Additional topics will be added from time to time
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