Projects Awarded in 2015

The Center’s mission is to increase the Environmental Health (EH) research portfolio at Mount Sinai and to bring non-EH researchers into the field through new transdisciplinary collaborations.

Title: “Predicting Neurotoxic Perturbations of Developmental Neuroplasticity via an Integrative Bioinformatics Approach”

PI: Joel Dudley

Neurodevelopment is marked by periods of activity-dependent neuroplasticity wherein neural circuitry is optimized by the environment. If these critical periods are perturbed, optimization of function (i.e. visual acuity or language) can be permanently disrupted. A major clinical and scientific gap is knowledge of environmental neurotoxicants that disrupt critical period biology. Historically, this knowledge has been limited by a lack of a comparable data shared between perturbagens and in vivo neuroplasticity and a lack of methods to systematically identify connections between the data. Here, we propose a novel integrative bioinformatics approach that leverages the exponential growth in public molecular data. Our goal is to systematically identify toxicants that suppress networks and pathways regulating critical periods of developmental neuroplasticity. In our preliminary study, we derived in vivo neuroplasticity signatures from mice with elevated plasticity in visual cortex, a well-established model of critical period plasticity. We then computationally matched these transcriptional signatures of in vivo neuroplasticity to >2500 curated toxicant gene set modules. We found overrepresentation of known (i.e. lead, toluene, arsenic, chlorpyrifos, methlymercury, PCBs) and novel neurotoxicants with neuroplasticity signatures. These results have led us to hypothesize that known (and novel) neurotoxicants will disrupt critical period neuroplasticity and result in molecular and functional consequences to neurological and cognitive development. We will test this hypothesis by first developing and applying an integrative informatics approach to identify and prioritize neurotoxicants based on transcriptional profiles (Aim1). We will then assess effect of known neurotoxicant (Pb2+) on developmental neuroplasticity using a well-characterized in vivo model of neuroplasticity (mouse visual system) (Aim2). Lastly, we will validate transcriptome-wide effect of anti-plasticity toxicants (Aim3). This work will establish the detrimental role of known neurotoxicants in developmental neuroplasticity and lay the groundwork for systematic, data-driven prediction and screening of novel neurodevelopmental toxicants.

 

Title: “Assessment of past phthalate exposure in adult rats using teeth microstructure analysis”

PI: Syam Andra

In this project we will use teeth microstructure analysis as a biomarker of past phthalate exposure in adult rats exposed in early life during critical windows for reproductive and metabolic programming. Wistar rat dams (N=12 litters/group) will be treated with vehicle control and 3 doses of either di-2(ethylhexyl) (DEHP) or di-nbutyl phthalate (DnBP) (0.018, 0.18, and 1.8 mmol/kg/day) from gestation day 13 to postnatal day 21 (weaning). Using an innovative approach based on tooth ontogeny and histological landmarks we will determine the concentrations of DEHP and DnBP metabolites in time-specific dentine layers of adult offspring rats reflecting in utero and lactational exposure. The techniques will combine fine microdissection of first mandibular rat teeth and analysis of phthalate metabolites by state-of-the-art high performance liquid chromatography-tandem mass spectrometry (HPLC/MS-MS). In addition, we will examine dose-responses for reproductive and metabolic effects in male rats, in particular disruption of androgen-dependent development and altered glucose homeostasis, and possible associations between these endpoints and internal phthalate doses assessed by teeth analysis. Overall, the transdisciplinary team of researchers involved in this project will combine unique expertise in the fields of developmental toxicology, epidemiology and analytical chemistry to establish an animal model that will validate the use of teeth as exposure biomarker that can assess longterm/late-onset effects of phthalates in relation to past exposure. The results obtained will reinforce the use of teeth as a potential biomarker of exposure in both animal and human studies, including ongoing birth cohort studies coordinated by the Department of Preventive Medicine at Mount Sinai.

 

Title: “Lead Exposure And Addictive Diseases: A Pilot Study Of The Association Between Tibia-Lead And Cocaine Addiction”

PI: Megan Horton

While researchers recognize several known risk factors for adult drug addiction (i.e., family history of addiction, physical and sexual abuse, depression and other co-morbidities), the role exposure to environmental chemicals may play in drug addiction has not been well studied. In this study, we propose to examine the association between environmental exposure to the heavy metal, lead, and cocaine addiction. The welldocumented neurotoxic cognitive and behavioral effects of environmental lead (Pb) exposure are attributed, in part, to disruption of the mesolimbic dopaminergic (DA) system. Animal studies demonstrate that low level Pb exposure results in excess synaptic DA, with consequent down-regulation of postsynaptic DA receptors. Disrupted DA function is a major player in mediating drug reward behaviors and the development of addiction to drugs of abuse, such as cocaine. Cocaine produces its immediate psychological effect by causing a build up of synaptic DA. We hypothesize that cumulative exposure to Pb is associated with increased drug seeking behaviors and a greater likelihood of cocaine addiction in humans. To test this hypothesis, we propose to pilot a case-control study of cocaine addicts and healthy controls enrolled in the ongoing Neuroimaging of Addiction and Related Conditions (NARC) Research Program. Using 109Cd-based K-shell X-Ray Fluorescence (XRF), we will measure cumulative Pb exposure in cases and controls and examine associations between Pb exposure and the neuropsychological and neuroimaging phenotypes of cocaine addiction. This study will help elucidate a novel toxicology-related mechanism of addiction, with potential applications to other disorders of self-regulation that are similarly characterized by compromised DA signaling, as well as to other environmental chemicals that act on the DA system. Results could inform insight into interventions addressing the environmental risk factors associated with vulnerability to addiction.

 

Title: “AIR QUALITY IN THE NEONATAL INTENSIVE CARE UNIT”

PI: Annemarie Stroustrup

Each year in the United States, over 300,000 neonates require admission to a neonatal intensive care unit (NICU) where they are exposed to a chemical-intensive hospital environment. Preterm infants spend a particularly vulnerable developmental period corresponding to the third trimester in the NICU. It is known that exposure to air pollutants including volatile organic compounds (VOCs) during fetal and early postnatal life can permanently alter pulmonary and neurobehavioral outcomes in children born at term. We also know that NICU graduates experience pulmonary and neurodevelopmental abnormalities at higher rates than the general population and may represent a highly vulnerable subpopulation for toxic chemical exposure. Neurodevelopmental and pulmonary disorders among NICU graduates are incompletely predicted by degree of prematurity or neonatal illness. There are no comprehensive studies of chemical exposure in the NICU. We do not understand the impact of hospital-based chemical exposure on clinical outcomes of NICU graduates. Specific source(s) and types of exposure need to be identified in order to mitigate potential adverse outcomes. We propose to leverage the NICU-Hospital Exposures And Long-Term Health (NICU-HEALTH) study to characterize inhalational chemical exposure in the NICU. The NICU-HEALTH study is an active prospective birth cohort study of moderately preterm infants in the Mount Sinai NICU. Information on exposure to medical materials and stress as well as serial biospecimens are collected from each infant throughout the NICU hospitalization. Short-term outcomes include growth and neurodevelopmental progress; long-term outcomes of neurodevelopment and pulmonary function are planned. No measures of air quality (AQ) are currently included in the NICU-HEALTH protocol. In the proposed study we will (1) evaluate both ambient AQ in the NICU and AQ inside the neonatal incubator; and (2) evaluate the association of AQ in the neonatal incubator with concurrent oxidative stress in hospitalized moderately preterm infants.

 

Title: “In utero chemical and non-chemical stressors, sex hormones, and infant neurodevelopment”

PI: Rosalind J. Wright

Despite increasing evidence that developing males and females respond differently to chemical and nonchemical stressors, few studies directly examine sex-specific effects of neurotoxicants. Moreover, the mechanisms underlying sex-specific effects of these toxicants are poorly understood. Chemicals and psychological stress both impact sex hormone physiology and differential exposure to sex steroids during prenatal development (e.g. altered testosterone, estradiol, progesterone levels) may represent a pathway to sex differences in neurodevelopment. Research in this area to date has been limited by a reliance on sex steroid assessment in single sample of saliva or amniotic fluid which can only represent sex steroid level over short periods of time. The proposed pilot analyses will take advantage of banked maternal saliva and hair samples from a subset (n=140) of mother-infant dyads participating in the PRogramming of Intergenerational Stress Mechanisms (PRISM) study to assess both diurnal fluctuations in sex steroids (representing daily rhythms of salivary testosterone, progesterone, and estradiol) and longer-term trait-like sex steroid levels measured in mothers’ hair collected shortly following delivery (representing integrated average levels over trimesters). The joint distribution of hair and salivary sex steroids will be assessed using advanced statistical approaches; combinations of sex steroid measures that are best associated with prenatal maternal stress and/or chemical exposures (metals, endocrine disrupting chemicals) will be determined. Associations between identified composite sex steroid indices and infant temperament, an early marker of infant neurodevelopment, will also be explored. We will compare the relative effectiveness of these derived prenatal sex steroid indices with respect to early neurobehavioral outcomes compared with conventional methods (single salivary measure or hair measure alone). This is the first study to assess the combined contributions of sex steroids measured in repeated saliva samples providing diurnal variation and in hair recreating exposure over the course of pregnancy in a longitudinal study examining infant neurodevelopment.