Genes & Environment in ADHD

 
         
 

compiledby Teresa Binstock for
Generation Rescue
June 2008

Genes & Environment in ADHD

 

Introduction: Significant assocations among environmental factors, attention deficit, and ADHD are increasingly described in peer-reviewed journals. Among these studies, many focus upon gene-alleles, pollutants, intra-cellular mechanisms, and rates of ADHD.  While perusing the abstracts, note that recent studies have documented numerous intra-body pollutants in every person so tested (reviewed in 38). A ramification is that the results of single-toxin studies may be diluted by the presence of other pollutants. Findings presented here make clear that many and perhaps most cases of AD and ADHD are not purely genetic in origin but arise from environmental factors and, in some cases, from their interplay with certain genes' allelic variants.


1. Smoking during pregnancy and offspring externalizing problems: an exploration of genetic and environmental confounds

D'Onofrio BM et al. 
Dev Psychopathol. 2008 Winter;20(1):139-64.

Previous studies have documented that smoking during pregnancy (SDP) is associated with offspring externalizing problems, even when measured covariates were used to control for possible confounds. However, the association may be because of nonmeasured environmental and genetic factors that increase risk for offspring externalizing problems. The current project used the National Longitudinal Survey of Youth and their children, ages 4-10 years, to explore the relations between SDP and offspring conduct problems (CPs), oppositional defiant problems (ODPs), and attention-deficit/hyperactivity problems (ADHPs) using methodological and statistical controls for confounds. When offspring were compared to their own siblings who differed in their exposure to prenatal nicotine, there was no effect of SDP on offspring CP and ODP. This suggests that SDP does not have a causal effect on offspring CP and ODP. There was a small association between SDP and ADHP, consistent with a causal effect of SDP, but the magnitude of the association was greatly reduced by methodological and statistical controls. Genetically informed analyses suggest that unmeasured environmental variables influencing both SDP and offspring externalizing behaviors account for the previously observed associations. That is, the current analyses imply that important unidentified environmental factors account for the association between SDP and offspring externalizing problems, not teratogenic effects of SDP.
PMID: 18211732


2. Psychiatric genetics: progress amid controversy

Burmeister M, McInnis MG, Zöllner S.
Nat Rev Genet. 2008 Jul;9(7):527-40.
http://www.nature.com/nrg/journal/v9/n7/pdf/nrg2381.pdf

Several psychiatric disorders--such as bipolar disorder, schizophrenia and autism--are highly heritable, yet identifying their genetic basis has been challenging, with most discoveries failing to be replicated. However, inroads have been made by the incorporation of intermediate traits (endophenotypes) and of environmental factors into genetic analyses, and through the identification of rare inherited variants and novel structural mutations. Current efforts aim to increase sample sizes by gathering larger samples for case-control studies or through meta-analyses of such studies. More attention on unique families, rare variants, and on incorporating environment and the emerging knowledge of biological function and pathways into genetic analysis is warranted.
PMID: 18560438


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3. Parallels between attention deficit hyperactivity disorder and behavioral deficits produced by neurotoxic exposure in monkeys

Rice DC.
Environ Health Perspect. 2000 Jun;108 Suppl 3:405-8.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1637819&blobtype=pdf

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.
PMID: 10852836


4. Etiologic subtypes of attention-deficit/hyperactivity disorder: brain imaging, molecular genetic and environmental factors and the dopamine hypothesis

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.
PMID: 17318414


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.
http://bjp.rcpsych.org/cgi/content/full/190/1/1

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.
PMID: 17197648


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.
PMID: 18522996


7. A genetic etiology of pervasive developmental disorder guides treatment

Solomon M, Hessl D, Chiu S, Hagerman R, Hendren R.
Am J Psychiatry. 2007 Apr;164(4):575-80.
http://ajp.psychiatryonline.org/cgi/content/full/164/4/575
PMID: 17403969


8. Dopamine: the rewarding years

Marsden CA.
Br J Pharmacol. 2006 Jan;147 Suppl 1:S136-44.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1760752&blobtype=pdf

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.
PMID: 16402097


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.
http://archpsyc.ama-assn.org/cgi/content/full/63/1/74

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 interaction.
PMID: 16389200


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.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1352384&blobtype=pdf

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.
PMID: 16375770


11. Smoking during pregnancy and the risk for hyperkinetic disorder in offspring

Linnet KM et al.
Pediatrics. 2005 Aug;116(2):462-7.
http://pediatrics.aappublications.org/cgi/content/full/116/2/462

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.
PMID: 16061604


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.
http://bjp.rcpsych.org/cgi/content/full/187/2/155

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 pregnancy.
PMID: 16055827


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.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=551167&blobtype=pdf

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.
PMID: 15798787


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.
PMID: 14657828


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.
http://content.nejm.org/cgi/content/abstract/335/11/783

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.
PMID: 8703183


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.
PMID: 9880446


17. Environmental exposure to polychlorinated biphenyls (PCBs) and dioxins. Consequences for longterm neurological and cognitive development of the child lactation

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.
PMID: 11065080


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.
PMID: 11815763


19. Human prenatal and postnatal exposure to polybrominated diphenyl ethers, polychlorinated biphenyls, polychlorobiphenylols, and pentachlorophenol

Guvenius DM et al.
Environ Health Perspect. 2003 Jul;111(9):1235-41.
http://www.ehponline.org/members/2003/5946/5946.html

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.
PMID: 12842779


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.
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.
PMID: 12361940


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.
http://www.ehponline.org/members/2001/109p605-611schantz/schantz-full.html

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.
PMID: 11445515


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.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1964891&blobtype=pdf

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 broader applicability.
PMID: 17805415


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.
PMID: 17280703


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.
http://www.jstage.jst.go.jp/article/bbb/69/10/1836/_pdf

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.
PMID: 16244432


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 transfer.
PMID: 12449328


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.
http://www.ehponline.org/members/2002/110p411-417sandau/sandau-full.html

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.
PMID: 11940460


27. Dietary exposure to polychlorinated biphenyls and dioxins from infancy until adulthood: A comparison between breast-feeding, toddler, and long-term exposure

Patandin S et al.
Environ Health Perspect. 1999 Jan;107(1):45-51.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=9872716

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.
PMID: 9872716


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.
PMID: 9828301


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.
http://www.ajph.org/cgi/reprint/87/10/1711

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 burden.
PMID: 9357362


30. Toxic threats to neurologic development of children

Schettler T.
Environ Health Perspect. 2001 Dec;109 Suppl 6:813-6.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1240616&blobtype=pdf

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.
PMID: 11744499


31. Poisoning young minds

Schmidt CW.
Environ Health Perspect. 1999 Jun;107(6):A302-7.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1566584&blobtype=pdf

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 policy making.
PMID: 10339457


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.
PMID: 18206700

33. Dopamine transporter genotype influences the physiological response to medication in ADHD

Gilbert DL et al.
Brain. 2006 Aug;129(Pt 8):2038-46.
http://brain.oxfordjournals.org/cgi/content/full/129/8/2038

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.
PMID: 16760197

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.
PMID: 17427196


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.
PMID: 10898903


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 pervasive aggression.
PMID: 15318027


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.
http://ajp.psychiatryonline.org/cgi/content/full/163/6/1103

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 childhood aggression.
PMID: 16741214


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.
http://autismstore.dyndns.org/Books-Children_with_Starving_Brains.html

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