FUTURE RESEARCH DIRECTIONS
We did not find any auditory deficits with PBDE doses that were equimolar to the PCB doses we have previously demonstrated to be ototoxic. However, given the
prevalence of PBDEs in the environment, it will be important for future studies to test higher doses of PBDEs to see if they cause auditory deficits. Other environmental chemicals are also known to disrupt the thyroid system, such as bisphenol A (BPA), for example (Zoeller et al., 2005), and they too should be tested for their potential to cause auditory deficits and/or to cause additive effects when animals are co-exposed. This is
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important for human health because very little is known about the potential for mixtures of chemicals that exist in the environment to have additive effects on auditory function.
Currently, we are examining if there are histological abnormalities in the cochlea of the rats developmentally exposed to PCBs that could play a role in both the auditory deficits and AGS we observed. Croften et al. (2000) has found that rats developmentally exposed to Aroclor 1254 showed a loss of OHCs in regions associated with the low frequency hearing loss they observed, with no other histological abnormalities to the rest of the organ of Corti. We would like to see if there are any structural abnormalities, such as a possible loss of OHCs, loss of ganglion cells, or an abnormal tectorial
membrane in developmentally PCB-exposed animals.
Future directions to elucidate if PCBs can interact with noise to increase the susceptibility to NIHL could include lowering the noise intensity to around 85dB, as no animals had any AGS at this level, and increasing the noise exposure time to 8 hours.
According to the NIOSH recommendations (1998), noise is potentially harmful starting at 85 dB over an 8-hour work day. Therefore that noise exposure procedure might be more relevant to humans.
One of the most surprising discoveries in this series of studies was that developmental PCB exposure markedly increases the susceptibility to AGS in
adulthood. This was a striking effect and a new discovery that has not been published in the previous PCB literature. Mechanistically, it would be interesting to look at GABA and glutamate levels in the inferior colliculus of PCB exposed animals, as
excitatory/inhibitory imbalances in that area of the brain have been shown to be important in the activation AGS (Eells et al., 2004; Faingold, 2002; Ishida et al., 1995;
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Kato et al., 1996). Although GABA and glutamate have not been studied in the inferior colliculus after PCB exposure, a previous study suggests that synaptosomes from PCB-exposed rats have reduced reuptake of glutamate and GABA (Mariussen and Fonnum, 2001). It would also be interesting to examine if postnatal thyroid hormone replacement in PCB rats could attenuate AGS susceptibility, similar to a study where postnatal thyroxine replacement was found to attenuate the hearing deficits seen PCB rats (Goldey and Crofton, 1998).
Only one other lab has published on the ability of perinatal exposure to PCBs to affect seizure susceptibility. They found a single PCB congener, PCB 95, to lower the threshold for forebrain seizures (Lein et al., 2010). It would be interesting to replicate those experiments using our environmentally relevant PCB mix (FRM). This would address whether early PCB exposure causes a generalized reduction in the seizure threshold, vs. a specific effect on AGS threshold. Possible experiments would include measuring field excitatory post-synaptic potentials (fESPS) from FRM-exposed
hippocampal slices to examine if they present epileptic waveforms, and conducting in vivo experiments using PTZ to examine whether FRM-exposed rats kindle after fewer repeated doses, or to examine if FRM-exposed rats have lower thresholds for forebrain seizures. If PCB mixtures are also shown to increase the susceptibility to forebrain seizures, then this would have very important human health implications.
In summary, although it is important to study the effects of single toxicants or risk factors, it is equally important to examine the interactions of relevant risks that humans are exposed to in everyday life. Through this series of studies, developmental exposure to an environmentally relevant toxicant, PCBs, has been shown to interact with other
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environmental chemicals and with loud noise to cause more detrimental outcomes than does exposure to PCBs alone. It is important to continue the study of interactions and co-exposures, as they may lead to important discoveries that will help us to gain a better understanding of human diseases.
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