Molly Kile: Environmental determinants of gains in school readiness for children aged 3-5
- Kim Anderson (Professor, Environmental & Molecular Toxicology, College of Agriculture and Life Sciences)
- Molly Kile (Assistant Professor in Environmental Safety Health Program, College of Public Health and Human Sciences)*
- Shannon Lipscomb (Assistant Professor in Human Development and Family Sciences, OSU-Cascades)
- Megan MacDonald (Assistant Professor in Movement Studies in Disability, College of Public Health and Human Sciences)
- Megan McClelland (Director of the Hallie Ford Center for Health Children and Families, Associate Professor in Human Development and Family Sciences and Methodology Core, College of Public Health and Human Sciences)
- Bo Zhang (Assistant Professor in Biostatistics Program, College of Public Health and Human Sciences)
Polybrominated diphenyl ethers (PBDEs) are widely used in building materials and consumer products as flame retardants. These compounds are not chemically bound to the product and can accumulate in the indoor environment through volatilization or as dust particles. These compounds resist degradation and persist in the environment which leads to their accumulation in human tissues. A cross-sectional, representative survey of the US population showed that at least one PBDE congener was detected in the blood of 97% of the population and that the PBDE concentrations were much higher in the US than in Europe (Sjodin et al 2008).
Young children appear to be particularly vulnerable to PBDE exposure because hand-to-mouth activity can lead to ingestion of PBDE-contaminated house dust. Experimental studies report that PBDEs are endocrine-disruptors, affect brain development including impaired learning and memory, as well as, altering behavior and that these adverse neurodevelopmental outcomes worsened with age (Darnerud, 2008; Bigsby et al, 1999; Costa and Giordano, 2007; Eriksson et al 2001, Suvorov and Takser, 2011, Viberg et al 2004). Only two epidemiological studies have been conducted. A prospective study, conducted in NY City after the September 11th terrorist attack, observed that prenatal exposure to PBDEs and PCBs were associated with adverse psychomotor and mental development in children aged 12 to 72 months (Herbstman et al 2010). Whereas, a prospective study in Spain reported that only postnatal exposure to PBDE was associated with increased risk of symptoms of attention deficit disorder and poor social competence, but not hyperactivity or cognitive or motor functions (Gascon et al, 2011). Given concerns that chemical exposures early in life may translate into long-term cognitive, emotional or behavioral deficits, we propose to evaluate the associations between PBDE exposure in 100 children aged 3 to 5 years old over the course of one school year.
The goals of this pilot study will be used to: 1) foster novel inter-disciplinary research across the College of Public Health and Human Sciences, the College of Agriculture and Life Sciences, and OSU-Cascades and collect data that will be, 2) determine feasibility of recruiting and retaining participants for a longitudinal environmental health study, and 3) generate pilot data that will be used to develop an R01 grant application to be submitted to the NIEHS that will propose to examine the association between environmental factors and neurodevelopmental outcomes that are relevant to children’s success in school.
Kim Anderson: Mobile Exposure Device: Tool and Method Development
Kim Anderson, Laurel Kincl, Dan Sudakin, Christopher Scaffidi (Engineering), Elena Peterson (PNNL)
Adaptation of several original individual developments by our team will be further innovated to develop an integrated MED (Mobile Exposure Device) to capture uniquely linked environmental-health information. Specifically one component is collection of both asthma-based endpoints based on spirometer measurements and location by GPS, with both data streams transmitted through smartphone applications. Concurrently we will assess the individual’s chemical exposure through the use of a chemical absorbing wristband that is a time-integrated and applicably time-linked to the clinical health and location information. The three data streams will be captured and integrated in order to discover statistical relationships among air pollutants, locations, and asthma conditions. The mobile exposure devices will be developed with input and testing with our community partners. The integrated data and relationships will be made available to our volunteers and partner community through cloud-based data visualization.
Project web page
Hong Molitor: Assessing A Zebrafish Model for In Vivo Delivery of Morpholino Oligomers
Antisense Morpholino oligomers (MOs) [1, 2] have revolutionary potential for treatment of a broad range of human diseases, including viral, bacterial, age-related and genetic diseases, but they suffer from poor systemic delivery into cells. MOs are widely used to knock down gene expression, modify pre-mRNA splicing or inhibit miRNA maturation and activity; injection of MOs into single-celled embryos of many creatures results in specific knockdown of targeted genes with little toxicity [3-6]. However, application of MOs in older animals have been very limited since injection of unmodified MOs into adult organisms results in little to no antisense activity . Conjugates of cell-penetrating peptides with MOs (CPP-MOs) [8-11] can enter cells from the bloodstream of adult rodents and knock down targeted genes [7, 12, 13] and have entered two clinical trials involving localized dosing (non-systemic). CPP-MOs enter cells far more effectively than unmodified MOs [7, 8, 12] but application of CPP-MOs is limited by their narrow therapeutic window , an index for estimation of the range of drug dosage which can treat disease effectively while staying within the safety range.
The toxicity of current CPP-MOs results in a narrow therapeutic window which precludes their use for systemic gene knockdown in humans. Optimizing the structure of the peptide component of the conjugates is expected to broaden the therapeutically useful dose range, opening the therapeutic window. Testing CPP-MOs in rodents is expensive and time-consuming; therefore, a high-throughput assay in an inexpensive vertebrate such as zebrafish will facilitate broader structure-activity screens of potential cell-penetrating peptides.
Recently, in collaboration with Dr. Karl Clark at Mayo Clinic, we have produced a novel transgenic zebrafish line with dual fluorescent protein reporters (Blue-Red fish). The fish line is currently hosted at SARL and expected to produce eggs within a month. The fish is designed to produce a transcript containing an in-frame blue fluorescent protein (BFP) cassette with a stop codon in one exon and in the next exon an red fluorescent protein (RFP) cassette. The BFP_RFP transcript is expressed ubiquitously from a beta-actin promoter. When produced together only mature BFP mRNA is expressed but the RFP is not translated. When a splice- modifying MO binds the transcript, the BFP cassette exon with its stop codon is spliced out, permitting RFP to be translated. Both decrease in BFP and increase in RFP are expected to be qualified and visualized by a PCR method and by a fluorescent microscope.
Our long-term goal is to solve the major barrier to bringing CPP-MOs to clinical trials as effective human therapeutics. The objectives of this proposal are to demonstrate that 1) CPP-MO conjugates will enter cells of the 2-day post-fertilization (dpf) Blue-Red zebrafish, knock down the BFP and up-regulate RFP; and 2) the fish model has a wide dynamic range to test the efficacy of the conjugates that containing several different CPP sequences. Our hypothesis is that the zebrafish with dual fluorescent protein reporters is a high-throughput and useful proxy for assessing systemic delivery of MO into cells of vertebrates body-wide.