Final Report: Pesticides, Endocrine Disruptors, Childhood Growth and Development (Birth Cohort)

EPA Grant Number: R831711C002
Subproject: this is subproject number 002 , established and managed by the Center Director under grant R831711
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Mount Sinai Center for Children’s Health and the Environment
Center Director: Wolff, Mary S.
Title: Pesticides, Endocrine Disruptors, Childhood Growth and Development (Birth Cohort)
Investigators: Wolff, Mary S. , Engel, Stephanie M.
Institution: Mount Sinai School of Medicine
EPA Project Officer: Callan, Richard
Project Period: November 1, 2003 through October 31, 2008 (Extended to October 31, 2010)
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2003) RFA Text |  Recipients Lists
Research Category: Children's Health , Health Effects , Health

Objective:

This progress report covers research during the period of 11/01/2003 through 10/31/2010. The aims of Project 2 (R831711C002)  were to utilize the existing longitudinal birth cohort to address the role of toxicant exposure (including pesticides, phthalates and bisphenol A) on childhood growth and development. To accomplish these aims, we extended follow-up of the original birth cohort of 404 maternal-fetal dyads (enrolled between 1998-2002) to include growth and neurodevelopmental assessments at approximately ages 4, 6, and 7-9 years. Given a delay in the start of funding for the renewed Center, some children had aged-out of the 4 year assessment (i.e., greater than 5.5 years) prior to the start of funding. However, they were re-contacted for the six year assessment as soon as they became age-eligible. We completed 148 4-year, 164 6-year, and 186 7-year visits. In total, we saw 188 of the original Project 2 birth cohort for a total of 365 visits, or approximately 70% of the children who returned for a 2-year visit at the end of the first MSSM Children's Center cycle (Year 1 visits n = 200, Year 2 visits n = 276).
 
Specific Aims:
  • To assess prenatal and postnatal exposures to potentially endocrine disrupting synthetic chemicals, specifically phthalates and bisphenol A (BPA), and their association with early and late childhood growth and neurodevelopment.
  • To assess prenatal and postnatal exposures to pesticides, particularly organophosphates and pyrethroids, and their relationships to long-term childhood growth and cognitive, motor and behavioral development.
  • To assess possible modulation of associations among pesticides, potentially endocrine disrupting chemicals, and childhood growth and neurodevelopment by genetically determined variation in individual susceptibility factors.

 

Summary/Accomplishments (Outputs/Outcomes):

At each visit, mothers completed the Behavior Rating Inventory of Executive Function (BRIEF) and the Behavioral Assessment Scale for Children (BASC). The BRIEF is designed to assess children's executive functioning in the home. The BASC is a global measure of a child's behavior and attention problems. At the 7-9 year visit we also administered the Social Responsiveness Scale (SRS), a questionnaire designed to identify characteristics of Autism Spectrum Disorder, including problems with interpersonal behavior, communication, and repetitive/stereotypic behaviors. The SRS is also validated for use in the general population.
 
Neurocognitive assessments, supervised by Dr. Richard Canfield, were customized to the age-range. At the 4-year visit children were administered a battery of assessments which provided measures of specific neuropsychological functions, including attention, learning, memory, and executive functioning. At the 6-year assessment we evaluated children's psychometric intelligence using the Wechsler Preschool and Primary School Scales of Intelligence, third edition (WPPSI-III, 2002), and at the 7-year visit we administered the WISC-IV to provide a common measure of cognitive performance across three Children's Centers and allow the possibility of future pooling of study participants between Columbia, Berkeley, and Mount Sinai.
 
We also provided a number of services to our participants to help address the issues of greatest concern to them. Each BASC was immediately scored by our research staff. Those with clinically significant scores in any domain were referred to our study psychologist for expert review. If the psychologist deemed it necessary, we contacted the parent and provided a referral to a low cost/no cost counseling service and offered to send a copy of their exam to their Pediatrician. We also provided copies of the WPPSI-III and/or WISC-IV to the parent if requested, and contacted parents whose children score greater than 1.5 standard deviations below the mean to suggest that they get in touch with their child's school principal for a full educational assessment. Large deviations between the full-scale IQ and specific sub-domains may indicate learning problems that could be addressed within the school system. Therefore, we looked for discrepancy patterns and offered to provide copies of all exams to parents for their child's school report.
 
Each visit also included detailed measurements of the child's growth, including weight, height, hip circumference, waist circumference, and lean body mass using the Tanita scale, which were provided to the parent at the end of the visit. Since growth measurements have been collected from each child from birth, we have a detailed trajectory of that child's growth. We created a growth report card for each child that was mailed out at the end of the study that included all of their growth measurements and their relationship to the CDC national sex- and age-specific norms.

Conclusions:

Specific Aim 1. To assess prenatal and postnatal exposures to potentially endocrine disrupting synthetic chemicals, specifically phthalates and bisphenol A (BPA), and their association with early and late childhood growth and neurodevelopment.
 
Highlights:
  • Prenatal Phthalates, Phenols and Fetal Growth:  Increased maternal prenatal low molecular weight phthalate (LMWP) metabolite concentrations were associated with increases in gestational age at delivery and head circumference. Increased concentrations of 2,5-dichlorobenzene and benzophenone-3 (BP-3) metabolites in prenatal urine were associated with decreased birthweight in boys and girls respectively. (Wolff et al. 2008) (Wolff et al. 2008)
  • Prenatal Phthalates and Neonatal Behavior:  Increased maternal prenatal concentrations of LMW and high molecular weight (HMW) phthalate metabolites were associated with abnormal neonatal Orientation, Motor, and Quality of Alertness domains as measured by the Brazelton Neonatal Behavioral Assessment Scale (BNBAS). These abnormalities also appeared to be sex-specific, with strong associations among girls, but not boys. (Engel et al. 2009)
  • Prenatal Phthalates and Childhood Behavior and Executive Functioning:  Increased prenatal LMWP metabolite concentration was associated with poorer scores on the BASC Aggression, Attention Problems, Conduct Problems, Depression, Adaptability, Externalizing Problems and Behavioral Symptoms Index, domains and composite scales. Poor scores in these domains tend to be associated with childhood Conduct Disorder, Depression, and Attention-Deficit Hyperactivity Disorder (ADHD) clinical groups. Increased prenatal LMWP exposure was also associated with poorer scores on the Emotional Control and Global Executive Composite indexes of the BRIEF. Phenols (including BPA) did not appear to be associated with the BASC or BRIEF domains. (Engel et al. 2010)
  • Prenatal Phthalates and SRS:  Increased LMWP concentration was associated with poorer total SRS scores. SRS treatment subscale scores were also significantly poorer for Cognition, Communication, and Awareness, but not for Mannerisms or Motivation. There were no associations for HMWP metabolites, which have lower exposure levels. Impaired social functioning is a salient feature of multiple behavior and developmental disorders and our findings may be applicable to those disorders as well. Phenols (including BPA) did not appear to be associated with the SRS. (Miodovnik et al. in press)
  • Prenatal Phthalates, Phenols and IQ:  There appear to be no consistent associations between phthalates or phenols and any of the WPPSI-III or WISC-IV cognitive domains. However, we are still in a preliminary stage of analysis, and modification by child sex has not yet been investigated.
  • Prenatal Phthalates, Phenols and childhood growth and growth trajectory:  There appear to be no associations between prenatal exposures to phthalates and phenols and childhood growth percentile z-score, in multivariate adjusted models. However, these analyses are in progress and we have not yet examined effect modification by infant sex.
 
Specific Aim 2. To assess prenatal and postnatal exposures to pesticides, particularly organophosphates and pyrethroids, and their relationships to long-term childhood growth and cognitive, motor and behavioral development.
 
Highlights:
  • Prenatal Pesticides and Neonatal Behavior.  Increased maternal prenatal concentrations of total diethylphosphates (DEP) and total dialkylphosphates (DAP) were associated with an increase in risk of abnormal reflexes, as was total dimethylphosphates (DMP) after paraoxonase 1 (PON1) expression was considered. There was a significant interaction between DMP and maternal PON1, which will be described under Specific Aim 3. (Engel et al. 2007)
  • Prenatal Pesticides and Cognitive Development:  Prenatal exposure to organophosphate pesticides has been shown to negatively impact child neurobehavioral development. Paraoxonase 1 (PON1) is a key enzyme in the metabolism of organophosphates. The Mount Sinai Children’s Environmental Health Study enrolled a multiethnic prenatal population in New York City between 1998 and 2002 (n = 404). Third trimester maternal urines were collected and analyzed for organophosphate metabolites (n = 360). Prenatal maternal blood was analyzed for PON1 activity and genotype. Children returned for neurodevelopment assessments at ages 12 months (n = 200), 24 months (n = 276), 6 to 9 (n = 169) years. Prenatal total dialkylphosphate metabolite level was associated with a decrement in mental development at 12 months among blacks and Hispanics. Effects were enhanced among children of mothers who carried the PON1 Q192R QQ genotype, which imparts slow catalytic activity. In later childhood, increasing prenatal total dialkyl- and dimethylphosphate metabolites were associated with decrements in perceptual reasoning in the maternal PON1 Q192R QQ genotype and followed monotonically decreasing trend with increasing prenatal exposure. Prenatal exposure to organophosphates negatively impacts cognitive development, which may begin at 12 months and continue through early childhood. A critical affected domain is perceptual reasoning. PON1 is an important mediating factor in identifying populations most susceptible to these deleterious effects.
  • Prenatal Pesticides Childhood Behavior and Executive Functioning:  Our preliminary analyses suggest that there is no association between prenatal pesticide exposure and childhood behavior and executive functioning, although detailed analyses have not yet been completed.
 
Specific Aim 3. To assess possible modulation of associations among pesticides, potentially endocrine disrupting chemicals and childhood growth and neurodevelopment by genetically determined variation in individual susceptibility factors.
 
Highlights:
  • Prenatal Phenols and Fetal Growth (Modification by infant sex):  Phenols are hormonally active. The impact of hormonally active chemicals on growth and development of the fetus may differ as a function of infant sex. We found strong interactions between infant sex and BP-3 and 2,5-dichlorobenzene exposure, such that increased exposure to BP-3 was associated with lower birthweight among girls (but not boys), and increased exposure to 2,5-dichlorobenzene was associated with lower birthweight among boys (but not girls). (Wolff et al. 2008)
  • Prenatal Pesticides and Behavior and Cognitive Development (Modification by PON1): Organophosphate pesticides are metabolized by PON1. At any given pesticide exposure level, the effective "dose" of pesticides that an infant is exposed to may be modified by how quickly pesticides are eliminated. There was a strong interaction between maternal PON1 expression level and total DMP on risk of abnormal neonatal reflexes, such that infants born to women in the first (interaction p ≤ 0.002) and second (interaction p ≤ 0.01) tertiles (slower metabolizers) had a greater risk of abnormal reflexes than infants of those in the highest tertile (fast metabolizers). For women in the highest tertile of PON1 expression, no increased risk of abnormal reflexes with increasing exposure was found. There was no interaction between total DEP and PON1. (Engel et al. 2007) (Engel et al. submitted)
  • Prenatal Phthalates and Neonatal Behavior (Modification by infant sex):  Phthalates are thought to be anti-androgenic. The distribution of testosterone and aromatase in the brain differs by infant sex. Therefore, neurological effects of phthalate exposure may differ as a function of infant sex. We identified interactions between prenatal phthalate exposure, infant sex, and neonatal behavior (interaction p < 0.1). Poorer performance on the Orientation and Quality of Alertness domains were limited to girls. Likewise, slightly improved motor performance was found only among boys. (Engel et al. 2009)
One very important finding that relates to all of the aims in the previous submission is that, consistent with our expectations, phthalate and phenol exposure in the urban environment are substantial and represent a major source of toxicant exposures to pregnant women and children.
 
All publications for this project are reported under the Final Report for the Center (see Final Report for Grant No. R831711).

Journal Articles:

No journal articles submitted with this report: View all 94 publications for this subproject

Supplemental Keywords:

Biochemistry, Chemicals, childhood development, children's environmental health, Children's Health, children's vulnerablity, endocrine disrupting chemicals, endocrine disruptors, Environmental Chemistry, Environmental Exposure & Risk, environmental health, environmental management, exposure pathways, exposure studies, fast food, Health, Health Risk Assessment, human health, lipase, neurodevelopment, neurodevelopmental toxicity, obesity, paraoxonase, pesticide exposure, pesticides, phthalates, pollutants/toxics, RFA, Risk Assessment, Scientific Discipline

, RFA, Health, Scientific Discipline, ENVIRONMENTAL MANAGEMENT, POLLUTANTS/TOXICS, Environmental Chemistry, Health Risk Assessment, Chemicals, Endocrine Disruptors - Environmental Exposure & Risk, endocrine disruptors, Biochemistry, Children's Health, Endocrine Disruptors - Human Health, Risk Assessment, environmental health, pesticide exposure, childhood development, pesticides, phtalates, endocrine disrupting chemicals, exposure studies, Human Health Risk Assessment, children's vulnerablity, neurodevelopmental toxicity, children's environmental health, exposure pathways

Progress and Final Reports:

Original Abstract
  • 2004 Progress Report
  • 2005 Progress Report
  • 2006 Progress Report
  • 2007 Progress Report
  • 2008
  • 2009

  • Main Center Abstract and Reports:

    R831711    Mount Sinai Center for Children’s Health and the Environment

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R831711C001 Growing Up Healthy in East Harlem (Community-Based Participatory Research)
    R831711C002 Pesticides, Endocrine Disruptors, Childhood Growth and Development (Birth Cohort)
    R831711C003 Genetics of Phthalate and Bisphenol A Risk in Minority Populations (Individual Susceptibility)