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Kelly J. Gauger,¹ Yoshihisa Kato,² Koichi Haraguchi,³ Hans-Joachim Lehmler,⁴ Larry W. Robertson,⁴ Ruby Bansal,¹ and R. Thomas Zoeller¹

¹Biology Department, Molecular and Cellular Biology Program, Morrill Science Center, University of Massachusetts, Amherst, Massachusetts, USA; ²School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; ³Daiichi College of Pharmaceutical Sciences, Fukuoka, Japan; ⁴Department of Occupational and Environmental Health, University of Iowa, College of Public Health, Iowa City, Iowa, USA

Abstract
Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants routinely found in human and animal tissues. Developmental exposure to PCBs is associated with neuropsychologic deficits, which may be related to effects on thyroid hormone (TH) signaling in the developing brain. However, PCBs may interfere with TH signaling solely by reducing circulating levels of TH, or they may exert direct effects on TH receptors (TRs) . Therefore, we tested whether maternal exposure to a commercial PCB mixture, Aroclor 1254 (A1254) , exerts effects in the fetal brain by one or both of these mechanisms. Dams were dosed daily with 0, 1, or 4 mg/kg A1254 from gestational day 6 (GD6) until they were sacrificed on GD16. A1254 significantly reduced circulating levels of triiodothyronine (T₃) and thyroxine (T₄) in pregnant rats but increased the expression of several TH-responsive genes in the fetal cortex, including neuroendocrine-specific protein A (NSP-A) , RC3/neurogranin, and Oct-1. These findings are consistent with a direct action of PCBs on TRs. However, we did not identify parent PCB congeners or metabolites that bound to rat TRs isolated from hepatic nuclei. These findings indicate that PCBs can interfere with TH signaling in the fetal brain by direct actions on the fetus rather than by producing maternal hypothyroidism. Key words: brain development, endocrine disruption, NSP-A, NSP-C, Oct-1, PCBs, RC3/neurogranin, thyroid, thyroid hormone. Environ Health Perspect 112:516-523 (2004) . doi:10.1289/ehp.6672 available via http://dx.doi.org/ [Online 22 December 2003]

Address correspondence to R.T. Zoeller, Biology Department, Molecular and Cellular Biology Program, University of Massachusetts, Amherst, MA 01003 USA. Telephone: (413) 545-2088. Fax: (413) 545-3243. E-mail: tzoeller@bio.umass.edu

We thank D. Darling and J. Meyer for their technical advice and R. Burch, A. Dowling, and D. Sharlin for comments on early versions of the manuscript.

This work was supported by grants ES10026 (R.T.Z.) and P42 ES 07380 (L.W.R. and H.-J.L.) from the National Institute of Environmental Health Sciences and grant T32MH47538 (K.G.) from the National Institute of Mental Health.

The authors declare they have no competing financial interests.

Received 14 August 2003 ; accepted 22 December 2003.