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Mount Sinai Center for Children's Environmental Health and Disease Prevention Research
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Principal Investigator: Mary
S. Wolff, PhD
Co-Principal investigator: Philip J. Landrigan MD,
MSc
| Overview | Results |
| Exposures and Outcomes | Community Partners |
| Research Projects | Selected Publications |
The Mount Sinai Center for Children’s Environmental Health and Disease Prevention Research was established in 1998 as an interdisciplinary Center to address the neurodevelopmental impacts of pesticides, lead and PCBs (polychlorinated biphenyls). The flexibility and infrastructure of the Center program made it possible to shift the focus to newly emerging toxins in the second 5-year cycle. The goals of the Center are to elucidate mechanisms of neurodevelopmental impairment in inner-city children and to investigate relationships between exposure to environmental factors, inner-city toxicants, genetic differences, fetal growth and development.
During years 1-5 of the Center, researchers studied effects of exposure to environmental chemicals on children’s growth and neurobehavioral development. Investigators characterized children’s exposures to pesticides, polychlorinated biphenyls (PCBs), DDT, chlordane and lead in three birth cohorts from East and Northern Harlem, New York City and evaluated susceptibility factors related to these exposures. With the East Harlem community, the Center developed, deployed and field-tested integrated pest management (IPM) methods to reduce children’s exposures to neurotoxic pesticides. In a population of African-American men whose mothers had participated in the Collaborative Perinatal Project during the 1960s, researchers measured in utero exposure to PCBs and found associated decrements in intelligence that were still evident at age 17 years.
In years 6-10, Mount Sinai Children’s Center researchers continue
to follow the birth cohorts established in the first grant cycle, to
evaluate effects on later childhood development of these prenatal exposures
as well as the prevalent ED exposures.
The three current projects in the Mount Sinai Children’s Center
address endocrine disruptors (EDs) and other factors in the urban “built
environment” – neighborhood characteristics, access to healthy
food and safe play spaces – that appear to influence the risk
of obesity, early onset of puberty in children, and possibly neurologic
function. The projects utilize precise measures of physical activity,
obesity and biomarkers (found in urine and saliva) of environmental
exposures as well as measures of individual susceptibility – genetic
polymorphisms in ED-related genes.
Primary Exposures: Inner-city toxicants, including pesticides and PCBs (1998-2003); Endocrine disruptors and factors in the urban built environment (2003-present)
Primary Outcome Measures: Body size, physical activity, neurodevelopmental impairment, biomarkers (urine and saliva), determinants of puberty including age at each stage of breast development, maternal and child stress.
Original Projects: 1998-2003
Project 1: Growing Up Healthy in East Harlem, Barbara Brenner, DrPH
This project enrolled 131 Black & Latina families into a study of pesticide and PCB exposure reduction and implementation of Integrated Pest Management (Growing Up Healthy in East Harlem).
Project 2: Exposure to Indoor Pesticides and PCBs and their effects on Growth and Neurodevelopment in Urban Children, Gertrud Berkowitz, PhD.
This project enrolled 404 families to study in utero exposure to pesticides and infant growth and neurodevelopment.
Project 3: Genetics of Chlorpyrifos Risk in Minority Populations, James Wetmur, PhD.
This project developed new high-throughput techniques for geno-, pheno-and haplotyping to assess metabolic capacity for organophosphate pesticides.
Project 4: Prenatal PCB Exposure and Neurodevelopmental Outcomes in Adolescence and Adulthood, Thomas Matte, MD.
This project evaluated neurologic and development measures through age 17 in relation to prenatal PCB exposure among 152 Black children with prenatal serum from 1960’s.
Project 5: Neuroendocrine Mechanisms of Environmental Toxicants During Development, Andrea C. Gore, PhD.
This project examined the effect of certain environmental toxicants on growth and GnRH neurons in female rats and in the GT1-7 neuronal cell lines.
Current Projects: 2003-2008
Project 1: “Growing
Up Healthy in East Harlem”
Project Leads: Barbara Brenner DrPH, Maida Galvez
MD
This project is examining the built-environment,
or neighborhood characteristics, associated endocrine
disruptor (ED) exposures, and their effects on
child growth and development.
- Original Abstract
- 2004 Progress Report
- 2005 Progress Report
- 2006 Progress Report
- 2007 Progress Report
Project 2: Pesticides,
Endocrine Disruptors, Childhood Growth and Development
Project Lead: Stephanie Engel PhD
This project is a prospective epidemiological
study to characterize associations between maternal exposures to EDs during
pregnancy and infant development in a birth cohort.
- Original Abstract
- 2004 Progress Report
- 2005 Progress Report
- 2006 Progress Report
- 2007 Progress Report
Project 3: Genetics
of Phthalate and Bisphenol A Risk In Minority Populations
Project Leads: James G. Wetmur PhD,
Jia Chen PhD
Investigators are continuing in this project to
develop measures of individual susceptibility, focusing on metabolism
of EDs. Studies of susceptibility factors in concert with environmental
exposures and in relation to development are being undertaken with families
in Project 2.
- Original Abstract
- 2004 Progress Report
- 2005 Progress Report
- 2006 Progress Report
- 2007 Progress Report
The Mount Sinai Children’s Center is also conducting the World Trade Center Pregnancy Outcome Study, following a cohort of women who were pregnant on 9/11/01 and were directly exposed to airborne toxicants at the WTC site. Among the factors being measured are child development, environmental exposures, maternal and child stress.
New Investigators: Maida Galvez MD, Susan Teitelbaum PhD
Biometry Core: James Godbold, PhD
Community Outreach: Luz Claudio, PhD
Notable research findings from the Mount Sinai Children’s Center include multiple contributions to a growing body of evidence that in utero pesticide exposures have adverse effects on birth size and child neurodevelopment. The Center mechanism has enabled exploration of multiple scientific disciplines to study exposure, susceptibility factors, and child health outcomes; to translate these to public health impact in consultation with the Centers for Disease Control and Prevention (CDC) and New York City Department of Health (NYCDOH); and to provide a training setting for resident environmental pediatric residents, fellow, and medical students.
Project 1 (1998-2008): Growing Up Healthy in East Harlem
In the first cycle (1998-2003), Project 1 developed, deployed and field tested Integrated Pest Management (IPM) and dietary modification strategies to reduce children’s exposure to neurotoxic chemicals.
- The community-based participatory research (CBPR) intervention project in East Harlem has demonstrated that it is possible to reduce residential use of pesticides in the inner city and to introduce Integrated Pest Management. Results have supported community and government policy in pesticide use and regulation (Brenner 2002, Brenner et al 2003).
- Infestations of cockroaches and pesticide use were reduced through the application of Integrated Pest Management at the household level compared with a control group who were provided with home safety training.
From 2003-2008, Project 2 built on earlier work, to enroll a new child cohort in East Harlem to investigate the role of the environment on childhood obesity. This project is a longitudinal study broadly examining whether endocrine disrupting chemicals, specifically phthalates and bisphenol A, and neighborhood factors are related, in East Harlem, New York. We examine how chemicals and neighborhood factors influence children’s diets, physical activity levels and subsequent risk for childhood obesity.
- We have found that inequities exist in food store availability by race/ethnicity within the community. Preliminary data indicate associations between food availability and children’s body size. 100% of African American Census blocks had neither supermarkets nor grocery stores.
- African American Census blocks were less likely to have convenience stores as compared to Racially mixed Census blocks while Latino Census blocks were more likely to have convenience stores, specialty food stores, full service restaurants and fast food restaurants.
East Harlem children have easy access to unhealthy foods:
- 55% live on a block with a bodega/convenience store
- 41% live on a block with fast food stores
The presence of bodegas on the same block as a child’s home was associated with a higher BMI-percentile.
- Children living on a block with one or more bodegas (range 1-6) were more likely to have a higher BMI-percentile compared with children having no bodegas on their block.
Endocrine Disruptor Exposures are Widespread
- Early results show very high (>100 μg/L median) urinary levels of metabolites of endocrine disrupting chemicals.
- A 6-month study of intra-child variability has shown that exposures are likely to be very steady over at least a year’s time in their lives.
- Important sources of these exposures have been determined using a product use questionnaire.
To better estimate factors in childhood growth, we are also assessing physical activity and resource availability for physical activity in East Harlem.
- Maps have been developed for play-spaces, open areas, and food sources in East Harlem, to use as measures of the built-environment in this community. These maps will be the basis of a study using Geographic Information Systems (GIS) to assess obesity and physical activity among children.
Project 2 (1998-2003): Exposure to Indoor Pesticides and PCBs and their effects on Growth and Neurodevelopment in Urban Children
- A prospective epidemiological study documented that babies exposed in utero to higher levels of organophosphate insecticides are smaller at birth; notably, decrements in birth weight and birth length are magnified with low expression levels of the pesticide-metabolizing enzyme paraoxonase (PON1). Smaller head circumference is strongly related to PON1, and for one pesticide metabolite an exposure effect was seen only with low-activity PON1. These are newly discovered gene-environment interactions. (Berkowitz et al 2003 ).
- This same cohort has found in utero organophosphate and DDE exposures to be associated with measures of neurodevelopmental delay up to age 7 in children. PON1 appears to modulate these effects.
- In utero exposure to organophosphates is associated with decreased head circumference of infants at birth, a risk factor for neurodevelopmental dysfunction in childhood. This effect was seen only in infants born to mothers with low expression levels of PON1, an esterase involved in detoxification of organophosphates (Wolff et al., in press).
- Maternal PCB levels in this cohort, albeit very low (median < 1 µg/L) were associated with fish intake. PCBs are of interest because they have been associated with neurological deficits in infants (Wolff et al. 2005).
Project 2 (1998-2003): Exposure to Indoor Pesticides and PCBs and their effects on Growth and Neurodevelopment in Urban Children
- A prospective epidemiological study documented that babies exposed in utero to higher levels of organophosphate insecticides are smaller at birth; notably, decrements in birth weight and birth length are magnified with low expression levels of the pesticide-metabolizing enzyme paraoxonase (PON1). Smaller head circumference is strongly related to PON1, and for one pesticide metabolite an exposure effect was seen only with low-activity PON1. These are newly discovered gene-environment interactions. (Berkowitz et al 2003 ).
- This same cohort has found in utero organophosphate and DDE exposures to be associated with measures of neurodevelopmental delay up to age 7 in children. PON1 appears to modulate these effects.
- In utero exposure to organophosphates is associated with decreased head circumference of infants at birth, a risk factor for neurodevelopmental dysfunction in childhood. This effect was seen only in infants born to mothers with low expression levels of PON1, an esterase involved in detoxification of organophosphates (Wolff et al., in press).
- Maternal PCB levels in this cohort, albeit very low (median < 1 µg/L) were associated with fish intake. PCBs are of interest because they have been associated with neurological deficits in infants (Wolff et al. 2005).
Project 2 (2003-2008): Pesticides, Endocrine Disruptors, Childhood Growth and Development
- We completed 343 follow-up visits on 188 children. Children were seen at approximately ages 4, 6 and 8 years. At each follow-up visit, child urine and maternal saliva were collected. Mothers were provided with questionnaires to complete while children were being assessed for growth and neurodevelopment. Mothers were asked to complete the BASC and the BRIEF behavioral and executive functioning questionnaires while they waited.
- Prenatal urines were analyzed for phthalate and phenol metabolites. Exposure levels were consistent with NHANES 2003 national levels.
- We have reported that low molecular weight phthalate metabolites had a positive association with gestational age at delivery and with infant head circumference at birth. Higher prenatal exposures to 2,5-dichlorophenol (2,5-DCP) predicted lower birth weight in boys (-210 g average birth weight difference between the third tertile and first tertile of 2,5-DCP; 95% CI, 71-348 g). Higher maternal benzophenone-3 (BP3) concentrations were associated with a similar decrease in birth weight among girls but with greater birth weight in boys. (Wolff MS et al., EHP 2008)
- We have reported significant effects in newborns on the Orientation and Motor domains and the overall Quality of Alertness score of the Brazelton Neonatal Behavioral Assessment Scale (BNBAS). Among girls, there was a significant linear decline in adjusted mean Orientation score with increasing urinary concentrations of high molecular weight phthalate metabolites (B = -0.37, p = 0.02). Likewise, there was a strong linear decline in their adjusted mean Quality of Alertness score (B = -0.48, p < 0.01). In addition, boys and girls demonstrated opposite patterns of association between low and high molecular weight phthalate metabolite concentrations and Motor performance, with some indication of improved Motor performance with increasing concentration of low molecular weight phthalate metabolites among boys. This is the first study to report an association between prenatal phthalate exposure and neurological effects in humans or animals, and as such requires replication. (Engel SM et al, ISEE 2008 abstract; manuscript under review)
- In preliminary analyses, we have also reported an association between increased prenatal low molecular weight phthalate exposure and poorer parent rating of childhood behavioral domains that are characteristically affected in childhood Conduct Disorder, Attention-Deficit Hyperactivity Disorder, and Depression clinical groups. Specifically, increased low molecular weight (LMW) phthalate metabolite concentrations were significantly associated with poorer BASC scores on the Aggression, Attention Problems, Conduct Problems, and Depression clinical scales; and Externalizing Problems and Behavioral Symptom Index composite scales. For the BRIEF, increased LMW phthalate concentrations were associated with poorer scores on the Global Executive Composite index, and the Emotional Control scale. These results extend our BNBAS findings, and suggest that long term neurodevelopmental consequences may result from prenatal exposure to these toxicants. (Engel SM et al., ISEE 2008 and SER abstracts; manuscript in preparation).
Project 3 (1998-2003): Genetics of Chlorpyrifos Risk in Minority Populations Mount Sinai researchers have been investigating gene-environment interactions and their impact on child development.
- PON1 (paraoxonase) is an enzyme which helps the body detoxify some organic compounds, including organophosphate (OP) pesticides and their metabolites, which can inhibit transmitters in the nervous system (such as acetylcholinesterase). Individuals exhibit a variety of levels of PON1 enzyme activity, resulting from genetic polymorphisms. Based on data from animal studies suggesting that exposure to pesticides in pregnancy and early life may impair growth and neurodevelopment, Mt. Sinai researchers studied how prenatal pesticide exposure could affect children. Pesticide exposure was assessed by a prenatal questionnaire administered to the mothers during the third trimester and analysis of maternal urinary levels of pesticides and metabolites, including chlorpyrifos and pyrethroids.
- Researchers reported that exposure to OP pesticides appears to interact with PON1 gene expression to alter fetal growth, and for mothers with low PON1 activity, a small reduction in the baby’s head circumference and head size were observed. This is especially significant for children’s health, because small head size can be predictive of subsequent cognitive ability and these data suggest that chlorpyrifos may have a detrimental effect on fetal neurodevelopment among mothers with low PON1 activity (Chen et al 2005).
- To investigate individual susceptibility to pesticides, researchers examined linkage of 5 PON SNPs, including PON2. By joining the genetic information with data on PON 1 activity in maternal prenatal blood and cord blood, we were able to demonstrate the greater susceptibility of newborns. Their PON1 activity was 1/3rd – 1/5th lower than their mothers. PON1 levels and infant-maternal proportions differed by race/ethnicity. For example, Caucasian infants with the CC promoter polymorphism in one SNP had >200% greater PON 1 activity than those with the alternate genotype (vs. TT). A grant from NIEHS on Haplotyping for Environmental Genomics was awarded to further develop this technology.
- Researchers have also developed high throughput techniques to allow rapid, accurate genotyping and phenotyping. In the birth cohort (Project 2), investigators found that PON1 genotypes contributed to a wide variation in the PON1 enzymatic activity in neonates and have developed a new single molecule-based haplotyping technology which could be exported to other laboratories. They have developed new high-throughput techniques for geno- and phenotyping of PON1 and other pesticide-metabolizing enzymes (Chen et al 2002, Wetmur et al 2005).
- Using these high-throughput techniques, polymorphisms in PON1 were characterized and phenotypes measured in three ethnic groups. Expression levels of PON1 are substantially lower in human infants than adults.
- We have developed a new robust single molecule-based haplotyping technology that should be easy to export to other laboratories. The technology was verified by showing haplotype-based variation in PON1 activity in mothers heterozygous at two loci, a result that could not have been determined by genotyping or by haplotype inference.
- Researchers at the Mount Sinai Children’s Center have also explored interrelationships of PON1 with serum lipids, as triglyceride levels contribute to individual levels of PON1 enzyme activity. Other studies have shown associations between fish intake and PCB levels. PCBs are of interest because they have been associated with neurological deficits in infants.
Project 3 (2003-2008): Genetics of Phthalate and Bisphenol A Risk In Minority Populations
- We characterized associations of 9 phenol biomarkers in urine with the UDP-glucuronosyltransferase 2B7 (UGT2B7) His268Tyr. UGT2B7 Tyr268 allele carriers had lower bisphenol A and triclosan urinary concentrations than non-carriers (p<0.05). These results indicate that genetic variation in a phase II enzyme for phenol metabolism may influence the relationship between exposure and biomarkers of exposure.
- We characterized associations of 10 phthalate biomarkers in urine and TagSNPS of the pancreatic and gastric lipases, PNLIP and LIPF respectively, and the same functional polymorphism in UGT2B7. Four TagSNPs in LIPF were associated with urinary exposure markers for the set of low molecular weight phthalate biomarkers. One PNLIP TagSNP was associated with exposure to DEHP, the major high molecular weight phthalate exposure (p<0.05). These trends were seen when analyses were carried out by haplotype. Five of the ten phthalate biomarkers were associated with UGT2B7 His268Tyr (p<0.05). These results indicate genetic variation in both phase I and phase II enzymes for phthalate metabolism may influence the relationship between exposure and biomarkers of exposure.
Boriken Neighborhood Health Center
The
Children’s Aid Society
East Harlem Community Health Committee
Little Sisters of the Assumption
Family Health Service
Mount Sinai and North
General Hospital Pediatric Clinics
Mount Sinai
School of Medicine Community Partnerships
Settlement Health
Union Settlement
Association
The main goal of the Mount Sinai Community Outreach and Translation Core (COTC)
is to develop, implement and evaluate strategies to translate scientific findings
on children’s environmental health into information that can be used by
the local community, policy makers and clinical professionals.
Berkowitz
GS, Wetmur JG, Birman-Deych E, Obel J, Lapinski RH, Godbold JH, Holzman
IR, Wolff MS 2004. In utero pesticide exposure, maternal paraoxonase
activity, and head circumference. Environ Health Perspect. 2004 Mar;112(3):388-91.
Borrell
LN, Factor-Litvak P, Wolff MS, Susser E, Matte
TD 2004. Effect of socioeconomic status
on exposures to polychlorinated biphenyls (PCBs)
and dichlorodiphenyldichloroethylene (DDE) among
pregnant African-American women. Arch Environ
Health. 2004 May;59(5):250-5.
Brenner
B 2002. Implementing a community intervention
program for health promotion. Soc Work Health
Care. 2002;35(1-2):359-75.
Brenner BL, Markowitz S, Rivera M, Romero H, Weeks M, Sanchez E, Deych E, Garg A, Godbold J, Wolff MS, Landrigan PJ, Berkowitz G 2003. Integrated pest management in an urban community: a successful partnership for prevention. Environ Health Perspect. 2003 Oct;111(13):1649-53.
Chen J, Chan W, Wallenstein S, Berkowitz G, Wetmur JG 2005. Haplotype-phenotype relationships of paraoxonase-1. Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):731-4.
Gore AC, Wu TJ, Oung T, Lee JB, Woller MJ 2002. A novel mechanism for endocrine-disrupting effects of polychlorinated biphenyls: direct effects on gonadotropin-releasing hormone neurones. J Neuroendocrinol. 2002 Oct;14(10):814-23.
Lamb
MR, Taylor S, Liu X, Wolff MS, Borrell L, Matte
TD, Susser ES, Factor-Litvak P 2006. Prenatal
exposure to polychlorinated biphenyls and postnatal
growth: a structural analysis. Environ Health
Perspect. 2006 May;114(5):779-85.
Longnecker
MP, Wolff MS, Gladen BC, Brock JW, Granjean P,
Jacobson JL, Korrick SA, Rogan WJ, Weisglas-Kuperus
N, Hertz-Picciotto I, Ayotte P, Stewart P, Winneke
G, Charles MJ, Jacobson SW, Dewailly E, Boersma
ER, Altshul LM, Heinzow B, Pagano JJ, Jensen
AA 2003. Comparison of polychlorinated biphenyls
(PCBs) levels across studies of human neurodevelopment.
Environ Health Persp 2003 111:65-70.
Wetmur
JG, Kumar M, Zhang L, Palomeque C, Wallenstein
S, Chen J 2005. Molecular haplotyping
by linking emulsion PCR: analysis of paraoxonase
1 haplotypes and phenotypes. Nucleic Acids
Res. 2005 May 10;33(8):2615-9.
Wolff
MS, Deych E, Ojo F, Berkowitz GS 2005. Predictors
of organochlorines in New York City pregnant
women, 1998-2001. Environ Res. 2005 Feb;97(2):170-7.
Wolff MS, Engel SM, Berkowitz GS, Teitelbaum S,
Siskind J, Barr DB, Wetmur J 2007. Prenatal
Pesticide and PCB Exposures and Birth Outcomes.
Pediatr Res, in press.
Full
List of Publications | Publications
List from NIEHS PubMed Database
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