Abstract
Objective: Dopamine function is sensitive to toxin exposure. The environmental toxin polychlorinated biphenyl (PCB) alters dopamine physiology in several, harmful ways. Intermediary signals include thyroid hormones as PCB exposure alters thyroid function leading to changes in dopamine neurochemistry. To compare PCB and thyroid alterations directly, we exposed rats perinatally to either PCB (25 ppm) or thiouracil (THIO; 0.625%) from gestational day 1 to separation from the dam at postnatal day (PND) 25 and examined a set of tests sensitive to dopamine function.
Methods: We measured behaviors including prepulse inhibition (PPI) of the acoustic startle response (ASR) in adulthood (60-90 PND) and ultrasonic vocalizations (USVs) during pup and adult periods. Dopamine levels in striatum were estimated using tyrosine hydroxylase immunohistochemistry and thyroid hormone levels were assayed in adulthood.
Results: Animals exposed to thiouracil had significantly elevated startle response and impaired PPI relative to controls and PCB exposed animals. This group also had significant reductions in both USV emission during PPI and tyrosine hydroxylase staining within striatum. Conversely, PCB exposure during the perinatal period did not lead to alterations in gating or dopamine levels in adulthood. Similar to previous studies using perinatal exposure to PCB or THIO, thyroid hormone levels were unchanged (THIO group) relative to controls or actually increased (PCB group) by adulthood.
Conclusion: The findings support an important role for thyroid function in dopamine-dependent behaviors. Results suggest PCB exposure leads to different outcomes in comparison to direct thyroid manipulations suggesting PCB exposure has distinct mechanisms of developmental hormone dysfunction and potential compensatory changes in response to endocrine disruption.
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References
Martin, C. A. et al. Ziram, a pesticide associated with increased risk for Parkinson's disease, differentially affects the presynaptic function of aminergic and glutamatergic nerve terminals at the Drosophila neuromuscular junction. Exp. Neurol. 275, 232–241 (2016).
Thiruchelvam, M., Richfield, E. K., Baggs, R. B., Tank, A. W. & Cory-Slechta, D. A. The Nigrostriatal Dopaminergic System as a Preferential Target of Repeated Exposures to Combined Paraquat and Maneb: Implications for Parkinson's Disease. J. Neurosci. 20, 9207–9214 (2000).
Seegal, R. F., Bush, B. & Shain, W. Lightly chlorinated ortho-substituted PCB congeners decrease dopamine in nonhuman primate brain and in tissue culture. Toxicol. Appl. Pharmacol. 106, 136–144 (1990).
Mariussen, E. & Fonnum, F. The effect of polychlorinated biphenyls on the high affinity uptake of the neurotransmitters, dopamine, serotonin, glutamate and GABA, into rat brain synaptosomes. Toxicology159, 11–21 (2001).
Mariussen, E., Andersson, P. L., Tysklind, M. & Fonnum, F. Effect of polychlorinated biphenyls on the uptake of dopamine into rat brain synaptic vesicles: a structure-activity study. Toxicol. Appl. Pharmacol. 175, 176–183 (2001).
Choksi, N. Y., Kodavanti, P. R., Tilson, H. A. & Booth, R. G. Effects of polychlorinated biphenyls (PCBs) on brain tyrosine hydroxylase activity and dopamine synthesis in rats. Fundam. Appl. Toxicol. 39, 76–80 (1997).
Lilienthal, H., Heikkinen, P., Andersson, P. L., van der Ven, L. T. & Viluksela, M. Dopamine-dependent behavior in adult rats after perinatal exposure to purity-controlled polychlorinated biphenyl congeners (PCB52 and PCB180). Toxicol. Lett. 224, 32–39 (2014).
Cromwell, H. C. & Berridge, K. C. Haloperidol decreases hyperkinetic paw treading induced by globus pallidus lesions in the rat. Exp. Neurol. 145, 288–294 (1997).
Roth-Harer, A. et al. Neurotransmitter concentrations and binding at dopamine receptors in rats after maternal exposure to 3,4,3',4'-tetrachlorobiphenyl: the role of reduced thyroid hormone concentrations. Environ. Toxicol. Pharmacol. 9, 103–115 (2001).
Meserve, L. A., Murray, B. A. & Landis, J. A. Influence of maternal ingestion of Aroclor 1254 (PCB) or FireMaster BP-6 (PBB) on unstimulated and stimulated corticosterone levels in young rats. Bull. Environ. Contam. Toxicol. 48, 715–720 (1992).
Corey, D. A., Juarez de Ku, L. M., Bingman, V. P. & Meserve, L. A. Effects of exposure to polychlorinated biphenyl (PCB) from conception on growth, and development of endocrine, neurochemical, and cognitive measures in 60 day old rats. Growth Dev. Aging60, 131–143 (1996).
Morse, D. C. et al. Interference of polychlorinated biphenyls in hepatic and brain thyroid hormone metabolism in fetal and neonatal rats. Toxicol. Appl. Pharmacol. 122, 27–33 (1993).
Zoeller, R. T., Dowling, A. L. & Vas, A. A. Developmental exposure to polychlorinated biphenyls exerts thyroid hormone-like effects on the expression of RC3/ neurogranin and myelin basic protein messenger ribo-nucleic acids in the developing rat brain. Endocrinology141, 181–189 (2000).
Cameron, D. L. & Crocker, A. D. Stimulation of D-1 dopamine receptors facilitates D-2 dopamine receptor recovery after irreversible receptor blockade. Neuropharmacology27, 447–450 (1988).
Crocker, A. D., Overstreet, D. H. & Crocker, J. M. Hypo thyroidism leads to increased dopamine receptor sensitivity and concentration. Pharmacol. Biochem. Behav. 24, 1593–1597 (1986).
Overstreet, D. H., Crocker, A. D., Lawson, C. A., McIntosh, G. H. & Crocker, J. M. Alterations in the dopami-nergic system and behaviour in rats reared on iodine-deficient diets. Pharmacol. Biochem. Behav. 21, 561–565 (1984).
Schwarzkopf, S. B., Mitra, T. & Bruno, J. P. Sensory gating in rats depleted of dopamine as neonates: potential relevance to findings in schizophrenic patients. Biol. Psychiatry31, 759–773 (1992).
Swerdlow, N. R., Braff, D. L. & Geyer, M. A. Sensorimotor gating of the startle reflex: what we said 25 years ago, what has happened since then, and what comes next. J. Psychopharmacol. 30, 1072–1081 (2016).
Geyer, M. A., Krebs-Thomson, K., Braff, D. L. & Swerdlow, N. R. Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl)156, 117–154 (2001).
Webber, E. S., Mankin, D. E., McGraw, J. J., Beckwith, T. J. & Cromwell, H. C. Ultrasonic vocalizations, predictability and sensorimotor gating in the rat. Behav. Brain Res. 253, 32–41 (2013).
Brudzynski, S. M. Ultrasonic calls of rats as indicator variables of negative or positive states: acetylcholine-dopamine interaction and acoustic coding. Behav. Brain Res. 182, 261–273 (2007).
Brudzynski, S. M. Pharmacology of Ultrasonic Vocalizations in adult Rats: Significance, Call Classification and Neural Substrate. Curr. Neuropharmacol. 13, 180–192 (2015).
Curran, C. P. et al. In utero and lactational exposure to PCBs in mice: adult offspring show altered learning and memory depending on Cyp1a2 and Ahr genotypes. Environ. Health Perspect. 119, 1286–1293 (2011).
Krishnan, D., Cromwell, H. C. & Meserve, L. Effects of polychlorinated biphenyl (PCB) exposure on response perseveration and ultrasonic vocalization emission in rat during development. Endocrine Disruptors2, e969608 (2014).
Nacci, D. et al. Evolution of tolerance to PCBs and susceptibility to a bacterial pathogen (Vibrio harveyi) in Atlantic killifish (Fundulus heteroclitus) from New Bedford (MA, USA) harbor. Environ. Pollut. 157, 857–864 (2009).
Corey, D. A., Juarez de Ku, L. M., Bingman, V. P. & Meserve, L. A. Effects of exposure to polychlorinated biphenyl (PCB) from conception on growth, and development of endocrine, neurochemical, and cognitive measures in 60 day old rats. Growth Dev. Aging60, 131–143 (1996).
Donahue, D. A., Dougherty, E. J. & Meserve, L. A. Influence of a combination of two tetrachlorobiphenyl congeners (PCB 47; PCB 77) on thyroid status, choline acetyltransferase (ChAT) activity, and short- and longterm memory in 30-day-old Sprague-Dawley rats. Toxicology203, 99–107 (2004).
Miller, M. D., Crofton, K. M., Rice, D. C. & Zoeller, R. T. Thyroid-disrupting chemicals: interpreting upstream biomarkers of adverse outcomes. Environ. Health Perspect. 117, 1033–1041 (2009).
Gauger, K. J. et al. Polychlorinated biphenyls (PCBs) exert thyroid hormone-like effects in the fetal rat brain but do not bind to thyroid hormone receptors. Environ. Health Perspect. 112, 516–523 (2004).
Provost, T. L., Juarez de Ku, L. M., Zender, C. & Meserve, L. A. Dose- and age-dependent alterations in choline acetyltransferase (ChAT) activity, learning and memory, and thyroid hormones in 15- and 30-day old rats exposed to 1.25 or 12.5 PPM polychlorinated biphenyl (PCB) beginning at conception. Prog. Neuropsychopharmacol. Biol. Psychiatry23, 915–928 (1999).
Juarez de Ku, L. M., Sharma-Stokkermans, M. & Meserve, L. A. Thyroxine normalizes polychlorinated biphenyl (PCB) dose-related depression of choline acetyltransferase (ChAT) activity in hippocampus and basal fore-brain of 15-day-old rats. Toxicology94, 19–30 (1994).
Seo, B. W. & Meserve, L. A. Effects of maternal ingestion of Aroclor 1254 (PCB) on the developmental pattern of oxygen consumption and body temperature in neonatal rats. Bull. Environ. Contam. Toxicol. 55, 22–28 (1995).
Cromwell, H. C. et al. Effects of polychlorinated biphenyls on maternal odor conditioning in rat pups. Physiol. Behav. 91, 658–666 (2007).
Jolous-Jamshidi, B., Cromwell, H. C., McFarland, A. M. & Meserve, L. A. Perinatal exposure to polychlorinated biphenyls alters social behaviors in rats. Toxicol. Lett. 199, 136–143 (2010).
Dover, E. N., Mankin, D. E., Cromwell, H. C., Phuntumart, V. & Meserve, L. A. Polychlorinated biphe nyl exposure alters oxytocin receptor gene expre ssion and maternal behavior in rat model. Endocrine Disruptors3, e979681 (2015).
Desai, A. N., McFarland, A., Cromwell, H. C. & Meserve, L. A. Influence of perinatal exposure to a poly-chlorinated biphenyl mixture on learning and memory, hippocampal size, and estrogen receptor-beta expression. Ohio J. Sci110, 114 (2010).
Porterfield, S. P. & Hendry, L. B. Impact of PCBs on thyroid hormone directed brain development. Toxicol. Ind. Health14, 103–120 (1998).
Ahmed, R. G., El-Gareib, A. W. & Shaker, H. M. Gestational 3,3',4,4',5-pentachlorobiphenyl (PCB 126) exposure disrupts fetoplacental unit: Fetal thyroid-cytokines dysfunction. Life Sci. 192, 213–220 (2018).
Suvorov, A. & Takser, L. Facing the challenge of data transfer from animal models to humans: the case of persistent organohalogens. Environ. Health7, 58 (2008).
Haave, M. et al. Long-term effects of environmentally relevant doses of 2,2',4,4',5,5' hexachlorobiphenyl (PCB153) on neurobehavioural development, health and spontaneous behaviour in maternally exposed mice. Behav. Brain Funct. 7, 3 (2011).
Park, H. K. et al. Factors associated with postoperative hypo thyroidism after lobectomy in papillary thyroid microcarcinoma patients. Endocr. Res. 40, 49–53 (2015).
Fielding, J. R. et al. Stimulation-evoked dopamine release in the nucleus accumbens following cocaine administration in rats perinatally exposed to polychlorinated biphenyls. Toxicol. Sci. 136, 144–153 (2013).
Miller, M. M., Sprowles, J. L. N., Voeller, J. N., Meyer, A. E. & Sable, H. J. K. Cocaine sensitization in adult Long-Evans rats perinatally exposed to polychlorinated biphenyls. Neurotoxicol. Teratol. 62, 34–41 (2017).
Miller, M. M., Meyer, A. E., Sprowles, J. L. & Sable, H. J. Cocaine self-administration in male and female rats perinatally exposed to PCBs: Evaluating drug use in an animal model of environmental contaminant expo sure. Exp. Clin. Psychopharmacol. 25, 114–124 (2017).
Hrdina, P. D., Ghosh, P. K., Rastogi, R. B. & Singhal, R. L. Ontogenic pattern of dopamine, acetylcholine, and acetylcholinesterase in the brains of normal and hypothyroid rats. Can. J. Physiol. Pharmacol. 53, 709–715 (1975).
Cameron, D. L. & Crocker, A. D. The hypothyroid rat as a model of increased sensitivity to dopamine receptor agonists. Pharmacol. Biochem. Behav. 37, 627–632 (1990).
Issy, A. C., Padovan-Neto, F. E., Lazzarini, M., Bortolanza, M. & Del-Bel, E. Disturbance of sensorimotor filtering in the 6-OHDA rodent model of Parkinson's disease. Life Sci. 125, 71–78 (2015).
Grant, L. M., Barnett, D. G., Doll, E. J., Leverson, G. & Ciucci, M. Relationships among rat ultrasonic vocalizations, behavioral measures of striatal dopamine loss, and striatal tyrosine hydroxylase immunoreactivity at acute and chronic time points following unilateral 6-hydroxydopamine-induced dopamine depletion. Behav. Brain Res. 291, 361–371 (2015).
Wada, H. & Seto, Y. Developmental effects of perinatal hypothyroidism on cognitive functions: focused on attention. Seishin Shinkeigaku Zasshi114, 949–956 (2012).
Wada, H., Yumoto, S. & Iso, H. Irreversible damage to auditory system functions caused by perinatal hypothy-roidism in rats. Neurotoxicol. Teratol. 37, 18–22 (2013).
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The work was partially funded by an award to HCC and LAM (the NIH/HHS/. United States R03 HD0536 92/HD/NICHD). In addition the work was partly funded by the departments of Biological Sciences and Psychology and the Center for Undergraduate Research at Bowling Green State University. We would like to thank Mr. Andy Wickiser for his help in designing apparatus and programming the prepulse inhibition chambers and undergraduate research assistants Micheal Stoffer and Kyle Shaw for their help in running the test sessions for prepulse inhibition.
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All procedures were approved by and performed according to the guidelines established by the Bowling Green State University Institutional Animal Care and Use Committee (IACUC) and United States Animal Welfare Act (7 U.S.C. §2131 et. seq.) as provided by the United States Research Council's Guide for the Care and Use of Laboratory Animals.
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Cynthia L. Toth declares that she has no conflicts of interest. David E. Mankin declares that he has no conflicts of interest. Katie A. Hiler declares that she has no conflicts of interest. Nicholas A.F. Baldwin declares that he has no conflicts of interest. Lee A. Meserve declares that he has no conflicts of interest. Howard C. Cromwell declares that he has no conflicts of interest.
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Toth, C.L., Mankin, D.E., Hiler, K.A. et al. Influence of Perinatal Polychlorinated Biphenyl or Thiouracil on Dopamine Function. Toxicol. Environ. Health Sci. 11, 283–294 (2019). https://doi.org/10.1007/s13530-019-0415-3
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DOI: https://doi.org/10.1007/s13530-019-0415-3