![[logo] US EPA](https://webarchive.library.unt.edu/eot2008/20090508050205im_/http://www.epa.gov/epafiles/images/logo_epaseal.gif){kind=logo}
University of Illinois FRIENDS Children's Environmental Health Center
Site Navigation
- Center Description
- Abstracts/Reports
- Publications
- Illinois Center Web Site
- University of Illinois – Department of Veterinary Biosciences
- The Texas A&M University System Health Science Center School of Rural Public Health
- Toxicology Research Center, SUNY at Buffalo
 |
Research Project Search
Principal Investigator: Susan L. Schantz
| Overview | Community Partners |
| Exposures and Outcomes | Selected Results |
| Research Projects | Selected Publications |
The FRIENDS (Fox River Environment and Diet Study) Children's Environmental Health Center at the University of Illinois, Urbana-Champaign, was established in 2001 to investigate the interactive effects of PCBs and methylmercury (MeHg) on cognitive, sensory and motor development in children.
The Center was created because of concerns about PCBs and methylmercury in the Fox River and other rivers and lakes in northeastern Wisconsin. These chemicals build up in the fish and people who eat these fish may absorb some of these chemicals. The population being studied consists of Hmong and Laotian refugees who settled in northeastern Wisconsin after the Vietnam War and who regularly consume fish from the Fox River. The goal of the FRIENDS Center is to find out how much locally caught fish these families eat, and whether children born to mothers who eat fish with PCBs and/or mercury have more health problems than children born to mothers who don’t eat the fish.
Projects include longitudinal assessment of a birth cohort exposed to these chemicals through maternal consumption of contaminated fish and complementary laboratory-based projects, including animal and in vitro models to determine the mechanisms through which these contaminants induce neurological deficits in children. An additional focus is to develop effective educational strategies to reduce exposure to these fish-borne contaminants.
The Center is the collaborative effort of investigators in epidemiology, toxicology, biostatistics, and developmental psychology from various institutions, including the University of Illinois at Urbana-Champaign, the University of Illinois at Chicago, Texas A&M University, the University of Oklahoma, the State University of New York at Buffalo, the New York State Department of Health, and Michigan State University, and includes an administrative core, a community-based project, two biomedical research projects and an analytical toxicology core.
Primary Exposures: Mercury and PCBs
Primary Outcomes: Neurodevelopment, including neuropsychological and auditory function, neurobehavioral effects
Project 1: Perinatal PCBs and Neuropsychological/Auditory Function
Project Leader: Anne M. Sweeney
The Center is focused on identifying these potential developmental
deficits, and is guided in several important ways through the
efforts of the program’s
supporting projects. Dr. Paul Kostyniak’s Analytical and Toxicology Core,
for example, has developed a mixture (the Fox River PCB Mix) that closely resembles
the PCB congener profile in fish participants are consuming from the Fox River.
This mixture is currently being fed to animals in Dr. Susan Schantz’s lab
to assess its impact on cognitive, motor and auditory function. Results from
these animal studies are being used to guide Dr. Sweeney and her team in the
selection of an appropriate battery of tests to administer to infants born in
the community-based study. In addition, the underlying mechanisms that could
explain how this mixture modifies brain development and neurochemistry are being
studied in Dr.
Richard Seegal’s lab.
Brian Powers, a graduate student working in the Schantz lab, found that rats exposed to the Fox River PCB Mix during early development suffered from permanent hearing loss. The results pointed to the cochlea, a coiled, shell-like structure within the ear, as the site of the damage. As a direct result of these laboratory findings, audiologists with the Green Bay research team are assessing cochlear function in newborn infants in the birth cohort.
Investigators are following these infants from birth to about age five looking at other domains such as working memory, attention, impulse control, motor balance, and very early verbal skills and knowledge, which could be affected by exposure to PCBs and other chemicals.
Project 2: Neurobehavioral Effects of PCBs and Methylmercury in Rats
Project Leader: Susan L. Schantz
Animal studies are an extremely important component of the FRIENDS Center. At the University of Illinois, Dr. Schantz and colleagues are using an animal model to assess the effects of developmental exposure to PCBs and methylmercury (MeHg).
In the lab, female rats are fed a mixture formulated to mimic actual human exposure to PCBs and MeHg from contaminated fish caught from the Fox River in Green Bay, Wisconsin. Exposure begins before pregnancy and continues through lactation until pups are weaned. In order to assess the effects of developmental PCB exposure, male and female offspring from each litter are tested on a battery of cognitive, motor, and auditory tests when they reach adulthood. The results are being used by the Center’s epidemiologists to guide the selection of outcome measures to be used in the children who are being followed in the community-based study.
Brian Powers, a graduate student in the Schantz lab, has observed auditory deficits in rats exposed to the Fox River PCB mixture during early development. In his study, two different tests of auditory function were employed: one assessed function of the peripheral sensory organ, the cochlea, and the other assessed central processing of auditory information as it travels from the cochlea through the brainstem.
The first test measured distortion product otoacoustic emissions, or DPOAEs, which are produced by the outer hair cells of the cochlea in response to sound. The second test measured the auditory brainstem response, or ABR—electrical activity produced in the brainstem in response to an auditory stimulus. The rats experienced permanent deficits in auditory function and the findings suggested that this was the result of damage to the cochlea. These data were used to develop a testing strategy which is currently being used to assess hearing in newborn infants in the community-based study.
In other research conducted with the siblings of the rats that under went the hearing tests, Dr. Helen Sable, a research assistant professor in the Schantz lab, showed that rats exposed to the Fox River PCB mix during early development had problems with inhibitiory control. When placed in an operant box with a lever to press, the rats had trouble “holding back” a response when one was not necessary or appropriate. Similar problems have been reported in PCB-exposed children and in children diagnosed with ADHD. In the future Dr. Sable hopes to investigate the effect of drugs used to treat ADHD on inhibitory control in PCB-exposed rats.
Project 3: Developmental Effects of PCBs and Methylmercury
Project Leader: Richard F. Seegal
This laboratory-based project directed by Dr. Richard Seegal will aid in understanding results obtained from the community based study by determining the mechanisms by which PCBs and methylmercury alter central nervous system function. Using a number of experimental models, including laboratory rodents and tissues from these animals, Dr. Seegal and his team are investigating the effects of PCBs and MeHg, both individually and in combination, on neurotransmitter systems in the brain responsible for learning and behavior.
So far, data that Dr. Seegal’s group has collected shows that the effects
of simultaneous exposure to these two neurotoxicants may be greater than the sum
of the effects of exposure to the toxicants individually. These studies
may have a significant impact on risk assessment decisions and the establishment
of advisories for the consumption of fish contaminated with the chemicals, he
says.
Dr. Seegal is also investigating the effects of PCBs and MeHg
at different times during development. Using pinched off nerve endings, called synaptosomes,
derived from animals of different ages and maintained in tissue culture, he has
observed that a critical period exists early in development where animals are
more susceptible to PCBs and MeHg. The turning point appears to be around the
time of weaning, and this finding may have potential correlates with humans.
In addition to these findings, Dr. Seegal has recently shown that methylmercury causes loss of cell viability, or cell death, through an oxidative stress-independent mechanism. Rather than methylmercury inducing oxidative stress leading to mitochondrial dysfunction, the oxidative stress appears to be further downstream, suggesting that treatment with antioxidants, may not be very effective as a protective treatment for methylmercury exposure.
Role of Reactive Oxygen Species
The role of the formation of reactive oxygen species (ROS) in mediating the PCB and MeHg effects on neuronal function is also being investigated. MeHg has been demonstrated to induce ROS formation in synaptosomes from postnatal day 7, 14, 21 and adult rats. Furthermore, the effects were more pronounced in the tissue from young rats. Researchers at the Illinois Children’s Center are investigating the effects of MeHg and ROS formation on mitochondrial function. It appears that mitochondrial membrane dysfunction is an early event in MeHg toxicity and that ROS formation may be an effect of that damage. These experiments will be expanded to assess the impact of combinations of PCBs and MeHg on mitochondrial function and ROS formation. Future studies will use approaches such as pharmacological challenges and in vivo microdialysis to investigate the extent to which these alterations in dopamine function observed in vitro are mediating the deficits in cognitive and motor function that have been observed in vivo.
PCB and MeHg Interactive Effects
An important goal of the Center’s laboratory animal research is to model PCB and MeHg exposure in the human population as closely as possible and to use findings from these animal studies to identify critical neurological outcomes to assess in exposed children. In particular, the focus is on outcomes such as auditory and motor function that have not been adequately addressed in previous studies.
Pilot studies assessed the effects of combined exposure to MeHg and Aroclor 1254 (a commercial PCB mixture) during early development on later cognitive, motor and auditory function in rats. Initial studies revealed an interactive effect of PCBs and MeHg on motor function (Roegge et al., 2004). While neither chemical alone had a significant impact on balance and coordination, exposure to a mixture of both chemicals resulted in a marked deficit. In contrast, exposure to either PCBs or MeHg resulted in significant deficits in spatial learning and memory, but exposure to both PCBs and MeHg did not result in a larger deficit than was seen with either chemical alone (Widholm et al., 2004). Auditory testing using distortion product otoacoustic emissions (DPOAEs), which assess the functional integrity of the cochlea and auditory brain stem responses (ABRs), which assess the integrity of auditory pathway from the auditory nerve to the cortex, revealed PCB-related deficits in cochlear function. MeHg at the very low doses administered in this initial study (approximately 50:1 ratio of PCBs to MeHg) did not impair auditory function, nor did it exacerbate the effects of PCBs on auditory function.
Center researchers have obtained data from the Wisconsin Department Natural Resources (WDNR) showing the pattern of PCB congeners in fish being consumed by the study population. We then mixed differing amounts of four commercial PCB mixtures to create an experimental PCB mixture that mimicked the PCB congener profile in the fish. This experimental mixture of PCBs will be used in all current and future laboratory studies. Another goal was to model the ratio of PCBs to MeHg in the fish consumed by our study population. Data from the WDNR suggested that a ratio of PCBs to MeHg of about 7 to 1 would be appropriate.
An initial study of auditory function using the experimental PCB mixture revealed highly significantly reductions in the amplitude of the cochlear response as well as large increases in the threshold for a cochlear response across a range of sound frequencies. There were also subtle reductions in the amplitude of the early peaks in the ABR waveform. These alterations could also be indicative of cochlear damage.
On the basis of the animal studies, we have designed an auditory assessment protocol for newborn babies in the prospective birth cohort that includes a thorough assessment of DPOAE amplitudes and thresholds across a range of sound frequencies as well as complimentary measurements of ABRs.
Animal studies to determine if exposure to MeHg in a 7 to 1 ratio of PCBs to MeHg will exacerbate the PCB-induced deficits in auditory function are currently underway. Future studies will focus on understanding the mechanisms through which PCBs and potentially MeHg alter cochlear function. Animal studies of cognitive and motor function using the experimental PCB mixture and the 7 to 1 ratio of PCBs to MeHg are currently in progress. As with the auditory findings, the results of these studies will be used to help us design cognitive and motor testing protocols for babies in the prospective birth cohort.
Mechanistic Studies and Effects on Dopamine Levels
Mechanistic laboratory studies using ex vivo and in vitro approaches are in progress to evaluate the effects of PCBs and MeHg, alone and in combination on neuronal function at various developmental stages. Results demonstrate that combined exposure to PCBs and MeHg results in a synergistic increase in media dopamine concentrations in brain tissue (striatal synaptosomes) from postnatal day 14 or 21 day rat pups, but a lack of an interaction in synaptosomes from postnatal day 7 pups. The effects in the day 14 and 21 synaptosomes are similar to the synergism previously observed in adult synaptosomes (Bemis and Seegal Env Health Perspec. 1999) and the mechanism for this effect appears to be inhibition of the dopamine transporter. Organotypic co-cultures are also being used to investigate the effect of PCBs and MeHg on the dopamine system. These co-cultures model the developing nigro-striatal dopamine system. In co-culture, dopamine neurons of the substantia nigra project to and innervate the striatal tissue in a manner similar to that observed in vivo. In these co-cultures, low micromolar concentrations of the experimental PCB mixture reduce the number of dopamine neurons in the substantia nigra, reduce striatal dopamine concentrations, and increase neuronal cell death.
A central aim of the community-based project is to develop intervention
and education strategies that will reduce PCB and MeHg exposure
in the Hmong and Lao community. This
intervention and education component (PDF) ,
directed by Dr. Vicky Persky, has focused on reducing the consumption
of contaminated fish.
A number of educational materials have been created including
a simplified fishing advisory English
version and and Hmong
version which is specific to the bodies of water most
frequently fished by this population and is available in Hmong
and Lao. An educational video was
also created to teach basic concepts about contaminants in fish,
instruct viewers how to use the fishing advisory and demonstrate
how to clean and prepare the fish so as to limit PCB exposure.
The video is available in either Hmong or Lao with closed
captioning in English. Other outreach activities include a
quarterly newsletter and
a yearly community open house.
- Rats exposed to the Fox River PCB mix during early development show permanent hearing loss (Powers et al. 2006).
Aguiar, A and Schantz, SL (in press). FRIENDS Children’s Environmental Health Research Center: Assessing the Risks to Children from Environmental PCB and MeHg Exposure. To be published in Learning Disabilities. Full Text (PDF) (96 KB, 33pp, about PDF)
Dreiem A, Gertz CC, Seegal RF. The effects of methylmercury on mitochondrial function and reactive oxygen species formation in rat striatal synaptosomes are age-dependent. Toxicology Science 2005;87:156-62. Abstract | Full Text (PDF)(96 KB, 33pp, about PDF) | PubMed
Kostyniak PJ, Hansen LG, Widholm JJ, Fitzpatrick RD, Olson JR, Helferich JL, Kim KH, Sable HJ, Seegal RF, Pessah IN, Schantz SL. Formulation and characterization of an experimental PCB mixture designed to mimic human exposure from contaminated fish. Toxicology Science 2005;88:400-11 Abstract | Full Text PDF (345 KB, 12pp, about PDF) | PubMed
Powers BE, Widholm JJ, Lasky RE, Schantz SL. Auditory deficits in rats exposed to an environmental PCB mixture during development. Toxicology Science 2006;89:415-22. Abstract | Full Text (PDF) (144 KB, 8pp, about PDF) | PubMed
Roegge CS, Schantz SL. Motor function following developmental exposure to PCBS and/or MEHG. Neurotoxicology and Teratology 2006;28:260-77. Abstract | Full Text (PDF) (177 KB, 52pp, about PDF) | PubMed
Roegge CS, Wang VC, Powers BE, Klintsova AY, Villareal S, Greenough WT, Schantz SL. Motor impairment in rats exposed to PCBs and methylmercury during early development. Toxicology Science 2004;77:315-24. Abstract | Full Text (PDF) (177 KB, 52pp, about PDF) | PubMed
Full List of Publications | Publications List from NIEHS PubMed Database
Centers Funded By: 