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Sex on Executive Functions in Children

Tanya E. Froehlich, Bruce P. Lanphear, Kim N. Dietrich, Deborah A. Cory-Slechta, Ning Wang,

and Robert S. Kahn

Background: Prior studies have examined independent effects of a dopamine receptor D4 polymorphism (DRD4-7) and lead exposure on executive functions but not their interaction or the role of sex as a modifier of their effects.

Methods: Multivariable analyses were used to examine effects of DRD4-7 genotype, 60-month blood lead level, and sex on spatial working memory, rule learning and reversal, spatial span, and planning for 174 children.

Results: DRD4-7 was associated with poorer spatial working memory, and increasing blood lead levels were associated with impaired rule learning and reversal, spatial span, and planning. Adverse effects of lead on planning and rule learning and reversal were seen primarily for boys. In addition, the effect of lead on rule learning and reversal was evident predominately for those lacking DRD4-7.

Conclusions: We observed independent effects of DRD4-7 and lead on various executive functions and modifications of lead effects by DRD4 genotype and sex.

Key Words:Dopamine genes, dopamine receptor D4/DRD4, exec-utive function, gene-environment interaction, lead, sex/gender

D

eficits in executive functions (EF)—the neurocognitive

processes responsible for planning and direction of activities— have been implicated in disorders such as attention-deficit/hyperactivity disorder (ADHD) (Sergeant et al. 2002). Although environmental and genetic factors have been independently linked to EF, little is known about their joint effects. Given its presence in prefrontal areas (Meador-Woodruff et al. 1997), the dopamine receptor D4 gene (DRD4) is a plausible contributor to EF, and its exon III 7-repeat form (DRD4-7) has been associated with ADHD (Faraone et al. 2001). However, investigations of the link between DRD4-7 and EF have had mixed results (Langley et al. 2004; Swanson et al. 2000), a fact that may reflect failure to account for variability in environmental exposures. Lead is a prevalent neurotoxicant associated with impaired EF, consistent with its impact on prefrontal regions (Trope et al. 2001). However, identification of the neurobehavioral effects of lead has been complicated by interindividual variability (Bellinger 2004), possibly due to inter-actions with genetic polymorphisms (Smith et al. 1995). An interaction between lead and DRD4 is plausible given that lead affects dopamine system function (Brockel and Cory-Slechta 1999). Sex differences may also contribute to the observed variability in the effects of lead and DRD4 on EF. Prior studies have suggested that male subjects are more vulnerable to the EF effects of lead (Ris et al. 2004) and that sex influences dopamine receptor density (Andersen and Teicher 2000).

We investigated the link between DRD4-7 and EF, and modification of this association by lead exposure, using a cohort for whom a main effect of lead was already documented (Canfield et al. 2004). In addition, we explored sex, DRD4, and lead interactions to determine whether lead and DRD4 genotype more strongly affect EF in male subjects.

Methods and Materials

Sample

Two hundred seventy-six children were enrolled during infancy for a prospective study of low lead exposure and neurobehavior (Lanphear et al. 1999), with EF outcomes mea-sured at 66 months. Seventeen were not eligible for neurobehav-ioral evaluation (3 died; 14 were excluded because caretakers were short-term, lacked English proficiency, had relocated, or declined participation). Of those eligible, 195 attended both 60-and 66-month visits. Of these, 174 had data for⬎1 EF test, lead level, and DRD4 genotype. Income, maternal education, and mean 6- to 24-month blood lead level were not significantly different between those included and not included in this study. The University of Rochester and Cincinnati Children’s Hospital Institutional Review Boards approved this study protocol. Outcomes

The Cambridge Neuropsychological Testing Automated Bat-tery (Luciana and Nelson 2002) was administered at 66 months old. Executive function domains assessed included spatial work-ing memory, rule learnwork-ing and reversal, spatial span, and plan-ning (Table 1).

Primary Predictors

The DRD4 exon III locus was genotyped following published protocols using blood-derived samples (Ebstein et al. 1996). Children with the DRD4-7 allele (DRD4-7⫹/⫹ or ⫹/⫺) were compared with all others (DRD4-7 ⫺/⫺) (Swanson et al. 2000). Participants’ 60-month blood lead level was selected a priori as this study’s primary lead variable because other data indicated that concurrent blood lead levels were more strongly associated with intelligence quotient (IQ) than 24-month or lifetime average levels (e.g., Chen et al. 2005).

From the Departments of Pediatrics (TEF, BPL, NW, RSK) and Environmental Health (KND), University of Cincinnati College of Medicine, Cincinnati, Ohio; and Department of Environmental and Occupational Medicine (DAC-S), University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey.

Address reprint requests to Tanya Froehlich, M.D., Cincinnati Children’s Hospital Medical Center, Mail Location 7035, 3333 Burnet Avenue, Cin-cinnati, OH 45229; E-mail: tanya.froehlich@cchmc.org.

Received June 1, 2006; revised August 28, 2006; accepted September 25, 2006.

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Covariates

Factors shown to be prior predictors of child cognition and/or widely used in studies of lead exposure (Canfield et al. 2003) were considered as possible covariates (Table 2).

Analyses

Bivariate associations were examined using analysis of vari-ance or the Pearson correlation coefficient. The main study questions—whether DRD4-7 is linked to poorer performance on EF tasks and whether this association is modified by lead exposure—were examined using multivariable linear regression. The initial regression models for each outcome contained DRD4 genotype, lead level, a lead-DRD4 interaction term, and covari-ates associated with each outcome at p ⬍ .20 in bivariate analyses. To increase model specificity, interaction terms and covariates withp⬎.20 in the initial multivariable models were removed (pattern of results did not vary between trimmed and untrimmed models). To test for interactions with sex, separate

multivariable regression models were created for male and female subjects. The significance of any differences observed in sex-stratified models was investigated via models incorporating lead-sex, DRD4-sex, and lead-DRD4-sex interactions. Regression diagnostics were performed and outliers with student residuals ⬎3 were excluded to determine if their inclusion altered results. Unless otherwise noted, findings from the full sample, including outliers, are reported.

Results

Sample Characteristics

Our sample was 49% female subjects, with mean lead level of 6.1 ⫹ 4.9 ␮ g/dL (Table 2). Thirty-four percent had the DRD4-7⫹/⫹ or⫹/⫺genotype. The DRD4-7 frequencies for black (21.3%) and non-Hispanic white (16.3%) children, our two biggest groups, were consistent with published frequen-cies (Gelernter et al. 1997) and were in Hardy-Weinberg equilibrium.

Table 1. Executive Function Subtests of the Cambridge Neuropsychological Testing Automated Battery Executive Function

Domain CANTAB Subtest Name Overview Task Components Performance Measures

Spatial Working Memory

Spatial Working Memory

Involves ability to retain spatial information and to manipulate remembered items in working memory

● Multiple boxes displayed on computer screen

● Child touches screen to find tokens hidden in boxes, trying not to return to boxes where a token was previously found

● Total errors

● Between-search errors (returning to a box that previously contained a token)

Rule Learning and Reversal

Intra-Extra Dimensional Set Shift

Tests ability to learn a rule and then shift one’s strategy in the face of new information

● Child views two stimuli and infers which is “correct” based on patterns of positive reinforcement

● Criterion for each stage is reached after the correct stimulus is chosen six times

● The stimulus that is reinforced is then changed, and child must infer the new rule based on computer feedback

● Number of stages completed (maximum⫽9)

● Total number of trials required to reach highest stage (limit of 50 per stage), adjusted for stages passed

Spatial Span Spatial Span Assesses the ability to take in, store, and recall information in a sequential order

● For each trial, 10 white squares are shown, some of which momentarily change color in a variable sequence

● Child must touch each square in the same order as they were originally colored by the computer

● Number of squares in the sequence increases from two at the start of the test to nine by the end

● Span length (maximum sequence length recalled)

● Total errors (number of times an incorrect box was chosen)

Planning Stockings of

Cambridge

Involves the ability to create a cognitive roadmap to reach a goal

● Child views two arrangements of colored balls and is told to move the balls in the lower

arrangement to copy the pattern of the upper one

● Task difficulty levels based on the fewest number of moves needed to match goal arrangement (e.g., “3-move problem” can be solved by moving the balls a minimum of three times)

● Number of problems solved in the minimum number of moves possible

● Mean number of moves needed to solve each difficulty level

CANTAB, Cambridge Neuropsychological Testing Automated Battery.

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Bivariate Analyses

The dopamine receptor D4 polymorphism DRD4-7 was sig-nificantly associated with poorer spatial working memory (Table 3). Increasing lead was associated with impairment in all four EF domains (p⬍.05).

Adjusted Regression Analyses

In adjusted analyses, DRD4-7 remained associated with poorer spatial working memory (Table 4, Figure 1). Lead was significantly associated with at least one measure of rule learning and reversal, spatial span, and planning. Compared with DRD4-7 children, those lacking DRD4-7 were more impaired by increas-ing lead for rule learnincreas-ing and reversal (total trials-adjusted lead-DRD4 interaction term p ⫽ .042) and spatial span (total errors lead-DRD4 interaction term p ⫽ .053) (Table 4).

Interactions with Sex

Sex-stratified analyses showed that increasing lead impaired planning for boys but not girls (lead-sex interaction termsp

.0008 for mean number of moves,p⫽.049 for problems solved) (Table 4, Figure 2).

A significant lead-DRD4 interaction was observed for rule learning and reversal for boys but not girls. Among boys, those with DRD4-7 appeared to perform worse at the lowest lead levels, but those lacking DRD4-7 were more impaired by increas-ing lead. This effect was not seen in girls (Table 4, Figure 3). Lead-DRD4-sex interaction terms were significant (p⫽.014 for total trials-adjusted,p⫽.037 for stages completed).

No significant lead-sex, DRD4-sex, or lead-DRD4-sex interac-tions were identified for spatial working memory or spatial span. Regression Diagnostics

Excluding outliers (⬍ 3, varying by outcome) had minimal impact on study results other than marginally weakening the association between DRD4 and spatial working memory total errors (p⫽.037 to .058).

Discussion

Our findings suggest that DRD4-7 is associated with impaired spatial working memory and increasing lead levels are associated with poorer rule learning and reversal, spatial span, and plan-ning. The adverse effects of lead were seen more prominently for boys and those lacking DRD4-7.

The link between DRD4-7 and poorer spatial working mem-ory aligned with expectations, given prior associations between DRD4-7 and impairment on two executive function tasks (Match-ing Familiar Figures and Trail Mak(Match-ing Test) (Langley et al. 2004; Waldman 2005) that may engage aspects of spatial working memory. Other studies suggesting improved performance for DRD4-7 patients have focused on different domains, such as sustained attention, response inhibition, and response time (Bell-grove et al. 2005; Fossella et al. 2002; Langley et al. 2004; Manor et al. 2002; Swanson et al. 2000).

Increasing lead was linked to impaired rule learning and reversal and spatial span only for those lacking DRD4-7. This unanticipated finding suggests that DRD4-7 may confer some element of protec-tion for certain EF in a lead-contaminated environment.

Adverse effects of lead on planning and rule learning and reversal were seen in boys but not girls, corroborating reported associations between lead and impaired Continuous Perfor-mance Test functioning for male subjects only (Ris et al. 2004). Neuroimaging findings have also demonstrated a sexual

dimor-Table 2. Means and Frequencies of Outcomes and Predictors

N % or Mean (SD) Outcomesa

Spatial Working Memory

Total Errors 172 29.0 (21.2)

Between-Search Errors 172 27.7 (19.8)

Rule Learning and Reversal

Stages Completed 174 6.4 (2.1) Total Trials-Adjusted 174 188.2 (81.2) Spatial Span Span Length 174 2.5 (.7) Total Errors 174 7.8 (3.0) Planning

Problems Solved in Minimum Number of

Moves 126 3.3 (1.5)

Mean Number of Moves-3 Move Problem 128 4.9 (1.3) Gene and Lead Predictors

DRD4-7b

⫹/⫹or⫹/⫺ 60 34%

⫺/⫺ 116 66%

60-Month Blood Lead Level (␮g/dL)c

176 6.1 (4.9) Sample Characteristics/Covariatesd

Child Sex

Female 87 49%

Male 89 51%

Child Age (Years) 176 5.6 (.1)

Child Race/Ethnicity African American 113 64% Hispanic 20 11% Other 13 8% White, non-Hispanic 30 17% Maternal IQe 169 80.9 (12.9)

Income (Per Year)

⬍$10,000 77 45% $10,000–20,000 50 29% ⬎$20,000 44 26% Maternal Education ⬍12 Years 64 36% 12 Years 58 33% ⬎12 Years 54 31%

Caregiver Marital Status

Unmarried 117 67%

Married 58 33%

Mom’s Age at Delivery 176 25.2 (6.5)

Total HOME Scoref

168 27.1 (7.0) Neonatal Intensive Care Unit Admission

Yes 14 8%

No 162 92%

Reported Prenatal Tobacco Exposure

Yes 39 22%

No 136 78%

Reported Prenatal Alcohol Exposure

Yes 17 10%

No 152 90%

Transferrin saturationg

169 23.1 (8.7)

DRD4-7, dopamine receptor D4 gene exon III 7-repeat allele; IQ, intelli-gence quotient; DRD4, dopamine receptor D4 gene.

aParticipants with both 60-month lead level and DRD4 genotyping. bParticipants with 60-month lead level and at least one executive function outcome.

cParticipants with DRD4 genotyping and at least one executive function outcome.

dParticipants with 60-month lead level, DRD4 genotyping, and at least one executive function outcome (totalNnot always equal to 176 due to missing data).

eAssessed using the Stanford-Binet Intelligence Scale-IV quick screening battery.

fThe Home Observation for Measurement of Environment Inventory (HOME) is a standardized measure of the family environment, including caregiver responsiveness and cognitive stimulation.

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phism in the impact of lead on EF areas: greater lead-related frontal and cingulate gray matter reductions were observed in male subjects than female subjects (Cecil et al, unpublished data, 2006).

Limitations

Due to the modest sample size, we may not have detected all DRD4, lead, and sex interactions. Conversely, some findings may

be false positives attributable to multiple comparisons. Nonethe-less, our results demonstrate consistency, with DRD4 associa-tions observed for both spatial working memory outcomes and evidence suggesting lead-DRD4 and lead-sex interactions seen in more than one EF domain. The problem of multiple comparisons is somewhat mitigated by the relative independence of our EF domains (Pearson correlation coefficients nonsignificant for the relevant domains).

Table 3. Association of Executive Function Outcomes with Sample Characteristics: Bivariate Analyses

Spatial Working Memory Rule Learning and Reversal Spatial Span

Planning Total Errors Between-Search Errors Stages Completed Total Trials-Adjusted Span Length Total Errorsa Problem Solved in Minimum Number of Moves Mean Number Moves-3 Move Problem

Group Means (ANOVA Results) DRD4–7 ⫹/⫹or⫹/⫺ 34.0c 32.1c 6.2 193.6 2.6 7.9 3.2 5.0 ⫺/⫺ 26.6c 25.6c 6.5 181.9 2.5 7.8 3.4 4.8 Child Sex Female 29.0 27.9 6.6e 176.8d 2.7c 7.8 3.5 4.8 Male 29.6 28.2 6.2e 197.8d 2.4c 7.9 3.3 4.9 Child Race Non-White 27.1 25.8 6.2c 194.7c 2.5c 7.8 3.2c 4.9d White 31.1 29.9 7.3c 149.5c 2.8c 7.8 4.0c 4.4d Maternal Education ⬍12 Years 31.4 30.0 6.3 194.4 2.4c 7.6e 3.0 5.0 12 Years 27.4 26.2 6.4 186.9 2.6c 7.6e 3.5 4.7 ⬎12 Years 29.0 27.7 6.5 178.6 2.7c 8.3e 3.6 4.9 Annual Income ⬍$10,000 34.1c 32.4c 6.2e 199.2c 2.4c 7.8 3.0e 5.2d $10,000–20,000 27.9c 26.7c 6.3e 191.1c 2.6c 7.7 3.5e 4.7d ⬎$20,000 23.9c 23.3c 6.9e 160.9c 2.8c 8.1 3.8e 4.5d Married No 28.8 28.2 6.2c 194.8c 2.4c 8.1c 3.2d 4.9 Yes 29.7 27.9 6.8c 168.8c 2.8c 7.3c 3.8d 4.6 Neonatal Intensive Care Unit Admission

Yes 26.5 25.5 5.5d 220.0d 2.5 8.3 2.8 5.0

No 27.9 26.7 6.5d 183.6d 2.6 7.8 3.4 4.8

Reported Prenatal Tobacco Exposure

Yes 29.6 28.4 6.7 180.9 2.5 7.5e 3.7 4.5e

No 29.3 28.1 6.3 189.0 2.6 8.0e 3.3 4.9e

Reported Prenatal Alcohol Exposure

Yes 24.8 24.1 7.0 163.1 2.5 8.0 3.4 4.9

No 29.2 27.9 6.4 185.8 2.6 7.8 3.4 4.8

Pearson Correlation Coefficients

Blood Lead – 60 Month .19c .19c .18c .18c .28c .07 .23c .24c

Child Age .07 .06 .13d .12e .07 .02 .05 .07

Maternal IQ ⫺.07 ⫺.07 .16c .22c .37c .04 .27c .10

Mom’s Age at Delivery .05 .06 .05 ⫺.05 .13d .17c .01 .08

Total HOMEbScore .01 .01 .08 .11e .37c .01 .29c .14e

Transferrin Saturation .04 .04 .01 ⫺.01 .03 ⫺.01 .11e .07

ANOVA, analysis of variance; DRD4-7, dopamine receptor D4 gene exon III 7-repeat allele; IQ, intelligence quotient. aAdjusted for span length.

bHome Observation for Measurement of Environment Inventory. cp.05.

d.05p.10. e.10p.20.

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Table 4. Adjusted Relationships Between Executive Function Outcomes, Blood Lead, DRD4 Genotype, and Lead-DRD4 Interactions Spatial Working Memory Rule Learning and Reversal

Spatial Span Planning Total Errorsa Between-Search Errorsa Stages Completedb Total

Trials-Adjustedc Span Lengthd Total Errorse

Problems Solved in Minimum Number Movesf

Mean Number Moves-3 Move Problemg

␤(SE) ␤(SE) ␤(SE) ␤(SE) ␤(SE) ␤(SE) ␤(SE) ␤(SE)

Whole Sample Without Interaction

Blood lead .51 (.34) .47 (.32) ⫺.06 (.03)j 2.56 (1.25)j .02 (.01)j .04 (.04) .06 (.04) .08 (.03)i

DRD4 7.09 (3.37)j 6.14 (3.16)k .16 (.33) 4.04 (12.84) .14 (.11) .14 (.36) .23 (.29) .22 (.25)

Whole Sample with Interaction

Blood lead .27 (.45) .23 (.42) ⫺.10 (.04)j 4.15 (1.55)i .02 (.01)k .10 (.05)j .04 (.05) .06 (.04) DRD4 3.72 (5.35) 2.83 (5.01) ⫺.72 (.52) 38.22 (18.61)j .10 (.17) .98 (.56)k .12 (.53) .06 (.44) Lead-DRD4 .53 (.65) .52 (.61) .09 (.06) ⫺4.70 (2.29)j .01 (.02) .13 (.07)k .07 (.08) .05 (.07) Boys Onlyh Blood lead .48 (.42) .42 (.39) .19 (.06)i 7.81 (2.45)i .02 (.01)k .04 (.06) .13 (.07)k .20 (.05)j DRD4 11.29 (4.50)j 10.76 (4.19)j 1.33 (.80)k 51.95 (30.94)k .26 (.14)k 1.04 (.66) .48 (.47) .19 (.35)

Lead-DRD4 — — .20 (.09)j 8.64 (3.36)j .08 (.07)

Girls Onlyh Blood lead .49 (.59) .48 (.56) .01 (.06) .46 (1.71) .03 (.02) .17 (.08)j .01 (.05) .002 (.04)

DRD4 2.86 (5.11) 1.53 (4.80) .17 (.68) 11.96 (21.17) .009 (.16) 1.08 (.96) .04 (.38) .14 (.34)

Lead-DRD4 — — ⫺.09 (.10) 2.06 (3.16) — ⫺.22 (.14) — —

Unstandardized regression coefficients [␤] and standard errors [SE].

DRD4, dopamine receptor D4 gene; NICU, neonatal intensive care unit; IQ, intelligence quotient; HOME, Home Observation for Measurement of Environment Inventory. aFinal models adjusted for income.

bWhole sample with and without interaction final models adjusted for NICU, sex; Boys only and Girls only final models adjusted for NICU.

cWhole sample without interaction final model adjusted for NICU, sex; Whole sample with interaction final model adjusted for NICU, sex, maternal IQ; Boys only and Girls only final models adjusted for NICU, maternal IQ.

dFinal models adjusted for HOME score, maternal IQ, race.

eFinal models adjusted for mom’s age at delivery, maternal education, marital status, span length. fFinal models adjusted for maternal IQ, transferrin saturation.

gFinal models adjusted for in utero tobacco exposure.

hLead-DRD4 interactions are reported in the sex-stratified models only if they were significant or borderline significant for either boys or girls or if their inclusion affected the significance of the lead or DRD4 main effect findings.

ip.01. j.01p.05. k.05p.10. Froehlich et al.

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Additional limitations include our inability to completely exclude that another polymorphism in linkage disequilibrium with DRD4-7 may play a key role in our findings. Furthermore, we cannot exclude the possibility of false-positive results due to population stratification in our racially heterogeneous sample. However, such confounding is unlikely because DRD4-7 fre-quencies did not differ by race (p ⫽ .49) and race was not significantly related to the outcomes in multivariable analyses. Finally, sample attrition may have biased our results. However, for attrition to have spuriously led to our findings regarding interactions, we would have to posit some unusual scenarios, such as that high-performing lead-exposed boys systematically dropped out of the study but high-performing lead-exposed girls preferentially remained.

Conclusions

Although emphasis has been placed on understanding how genetic and environmental factors act in concert to produce neuropathology (Rutter et al. 2006), to our knowledge this study is the first to suggest that lead effects on EF are modified by genes in conjunction with sex. Although our findings are exploratory and warrant replication, they offer a model for future study of multilevel interactions in neurobehavioral dysfunction.

Grants supporting this work include National Institute of Envi-ronmental Health Sciences (NIEHS) R01 ES08388 (BPL), National Institute of Child Health and Human Development (NICHD) HD40362 (BPL), HD41141 (BPL), National Research Service Award (NRSA) 1T32PE10027 (TEF), National Institutes of Health (NIH) K23-HD40362-01 (RSK), Robert Wood Johnson Generalist Physician Faculty Scholars Award (RSK), and NIH/U.S. Environ-mental Protection Agency (EPA) P01-ES11261 (BPL).

Study findings were presented at the Pediatric Academic Society Annual Meeting on May 1, 2006.

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Figure 1.Spatial working memory performance for DRD4-7 and non-7 children, adjusted for 60-month lead level and income. DRD4-7, dopamine receptor D4 gene exon III 7-repeat allele.

0 1 2 3 4 5 6 7 0 2 4 6 8 10 12 14

Blood Lead Level (µg/dL)

M e a n # M o v e s t o S o lv e P ro b le m Boys Girls lead-sex p=0.0008

Figure 2.Planning performance (mean number of moves to solve three-move problem) stratified by sex as blood lead increases from 5th (1.3␮g/dL) to 95th (14.3␮g/dL) percentile in the sample, with results adjusted for prenatal tobacco exposure. For boys, change of lead from 0 to 10␮g/dL resulted in a 1.5 SD decline in performance.

0 50 100 150 200 250 300 0 2 4 6 8 10 12 14

Blood Lead Level (µg/dL)

Tot a l Tri a ls -A dj us te d

DRD4-7 Boys Non-DRD4-7 Boys

lead-DRD4 p=0.014 0 50 100 150 200 250 0 2 4 6 8 10 12 14

Blood Lead Level (µg/dL)

Tot a l Tri a ls -A dj us te d

DRD4-7 Girls Non-DRD4-7 Girls

lead-DRD4 p=0.35

Figure 3. Rule learning and reversal performance (total trials-adjusted) stratified by sex and DRD4 genotype as lead increases from 5th (1.3␮g/dL) to 95th (14.3␮g/dL) percentile in the sample, with results adjusted for maternal IQ and Neonatal Intensive Care Unit admission. For boys lacking DRD4-7, change of lead from 0 to10␮g/dL resulted in⬃1 SD decline in performance. DRD4, dopamine receptor D4 gene; IQ, intelligence quotient; DRD4-7, dopamine receptor D4 gene exon III 7-repeat allele.

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Figure

Table 1. Executive Function Subtests of the Cambridge Neuropsychological Testing Automated Battery Executive Function
Table 3. Association of Executive Function Outcomes with Sample Characteristics: Bivariate Analyses
Table 4. Adjusted Relationships Between Executive Function Outcomes, Blood Lead, DRD4 Genotype, and Lead-DRD4 Interactions Spatial Working Memory Rule Learning and Reversal
Figure 1. Spatial working memory performance for DRD4-7 and non-7 children, adjusted for 60-month lead level and income

References

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