2005 Progress Report: Neurobehavioral Effects of PCBs and Methylmercury in RatsEPA Grant Number: R829390C001
Subproject: this is subproject number 001 , established and managed by the Center Director under grant R829390
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: CECEHDPR - University of Illinois FRIENDS Children’s Environmental Health Center
Center Director: Schantz, Susan L.
Title: Neurobehavioral Effects of PCBs and Methylmercury in Rats
Investigators: Schantz, Susan L.
Institution: University of Illinois at Urbana
EPA Project Officer: Hahn, Intaek
Project Period: October 17, 2001 through October 16, 2002
Project Period Covered by this Report: October 17, 2004 through October 16, 2005
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2001) RFA Text | Recipients Lists
Research Category: Children's Health , Health Effects , Health
The objectives of this research project are to: (1) characterize the cognitive, motor, and sensory effects of perinatal exposure to polychlorinated biphenyls (PCBs) alone, methylmercury (MeHg) alone, or PCBs and MeHg in combination in the laboratory rat; (2) investigate the role of changes in specific neurotransmitter systems in mediating specific behavioral effects; (3) investigate the role of altered thyroid hormones in mediating specific behavioral effects; and (4) use the results from these animal experiments to guide the selection of behavioral tests for use in children exposed to PCBs and MeHg through maternal consumption of contaminated fish.
Initial dose-effect studies using the newly formulated Fox River PCB mix, which closely models the PCB exposure profile in the fish being consumed by our human cohort, were completed in early 2005 (Objective 1). Female Long-Evans rats were exposed to 0, 1, 3, or 6 mg/kg/day of the Fox River PCB mix beginning 4 weeks prior to breeding and continuing throughout gestation and lactation. Pups were weaned at 21 days of age, and four pups—two males and two females—were retained for cognitive, motor, and auditory assessments. Cognitive and motor data currently are undergoing statistical analysis and will be submitted for publication during the coming grant year.
The auditory data have been analyzed, statistically and a paper is in preparation for submission to Toxicological Sciences. Hearing was assessed when the animals were young adults using three complementary approaches: (1) distortion product otoacoustic emissions (DPOAEs) were used to assess the functional integrity of the cochlea; (2) auditory brain stem responses (ABRs) were used to assess the integrity of the auditory pathway from the auditory nerve to the cortex; and (3) an operant learning task was used to assess hearing thresholds behaviorally.
It is believed that PCBs affect hearing by damaging the outer hair cells of the cochlea. Thus, we hypothesized that DPOAEs would be a particularly sensitive method for measuring PCB-induced hearing loss. This was confirmed in our research. All three doses of PCBs significantly reduced the amplitude of the cochlear response and increased the threshold for a cochlear response across a range of frequencies (Figure 1). The high dose resulted in a 40 percent reduction in the amplitude of the distortion product. There also were subtle reductions in the amplitude of the early peaks in the ABR wave form. These alterations also could be indicative of cochlear damage. Behavioral threshold data currently are undergoing statistical analysis.
Figure 1. Amplitude and Threshold Versus Frequency of the Cochlear Response
On the basis of these animal studies, we have designed an auditory assessment protocol for newborn babies in our prospective birth cohort, which includes a thorough assessment of DPOAEs across a range of frequencies as well as measurements of ABRs. The protocol was developed in consultation with two pediatric audiologists, Robert Lasky from the University of Texas Health Sciences Center at Houston and Cynthia Fowler from the University of Wisconsin. Appropriate assessment equipment has been purchased, and clinical audiology consultants in Green Bay and Appleton have been hired to do the assessments. Training of the audiologists will occur over the summer, and the babies to be assessed will be born beginning in September 2005.
Studies evaluating combined exposure to MeHg and the Fox River PCB mix were initiated in 2004 (Objective 2). Adult female Long-Evans rats were exposed to PCBs alone (1 or 3 mg/kg/day), MeHg alone (0.4 or 4.0 ppm in the drinking water), 1 mg/kg/day of PCBs together with 1.5 ppm MeHg, 3 mg/kg/day of PCBs together with 4.5 ppm MeHg, or corn oil vehicle and plain tap water. The ratio of PCBs to MeHg was selected to model the ratio of PCBs to MeHg in Fox River fish. As in the earlier study, the females were exposed for 4 weeks prior to breeding and continuing throughout gestation and lactation. These studies currently are ongoing. Animals will be tested on the same battery of cognitive, motor, and auditory tests used in the earlier dose-effect PCB study. These data will allow us to assess the potential for additive or interactive effects from combined exposure to PCBs and MeHg. The results will be used to modify and refine further the battery of tests that will be used to assess neurobehavioral function in infants from the prospective birth cohort. Brain tissue from littermates of the animals that are being assessed for neurobehavioral effects will be shared with Dr. Richard Seegal (R829390C004) for analysis of dopamine and metabolites in specific brain regions.
During Year 5 of the project, the study of combined PCB and MeHg exposure will be completed, data will be analyzed, and manuscripts will be submitted for publication. In addition, drug challenge studies will be initiated to assess the role of the dopamine system in mediating neurocognitive changes following exposure (Objective 3), and thyroid hormone replacement studies will be initiated to assess the role of thyroid hormones in mediating the auditory and motor effects of PCB exposure (Objective 4).
Journal Articles on this Report : 2 Displayed | Download in RIS Format
|Other subproject views:||All 15 publications||5 publications in selected types||All 5 journal articles|
|Other center views:||All 38 publications||22 publications in selected types||All 21 journal articles|
||Roegge CS, Morris JR, Villareal S, Wang VC, Powers BE, Klintsova AY, Greenough WT, Pessah IN, Schantz SL. Purkinje cell and cerebellar effects following developmental exposure to PCBs and/or MeHg. Neurotoxicology and Teratology 2006;28(1):74-85.||
||Roegge CS, Schantz SL. Motor function following developmental exposure to PCBS and/or MEHG. Neurotoxicology and Teratology 2006;28(2):260-277.||
Supplemental Keywords:children’s health, disease and cumulative effects, ecological risk assessment, susceptibility, sensitive population, toxicology, Fox River, PCBs, exposure assessment, heavy metals, methylmercury, pesticides, fish consumption,, RFA, Scientific Discipline, Health, PHYSICAL ASPECTS, ENVIRONMENTAL MANAGEMENT, Health Risk Assessment, Environmental Chemistry, Epidemiology, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Physical Processes, Molecular Biology/Genetics, Children's Health, genetic susceptability, Risk Assessment, developmental neurotoxicology, neurotoxic, sensitive populations, childhood cancer, biomarkers, animal model, developmental effects, exposure, PCBs, Human Health Risk Assessment, children, assessment of exposure, children's vulnerablity, residential populations, methylmercury, PCB, neurodevelopmental toxicity, human exposure, neurobehavioral effects, biological markers, neurotransmitters, toxics
Progress and Final Reports:Original Abstract
Main Center Abstract and Reports:R829390 CECEHDPR - University of Illinois FRIENDS Children’s Environmental Health Center
Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R829390C001 Neurobehavioral Effects of PCBs and Methylmercury in Rats
R829390C002 Perinatal PCB Exposure and Neuropsychological/Auditory Function
R829390C003 FRIENDS Analytical Toxicology Core Facility
R829390C004 Developmental Effects of PCBs and Methylmercury