PMID- 22791642 OWN - NLM STAT- MEDLINE DCOM- 20130213 LR - 20211203 IS - 1899-1505 (Electronic) IS - 0867-5910 (Linking) VI - 63 IP - 3 DP - 2012 Jun TI - Sex-dependent changes in cerebellar thyroid hormone-dependent gene expression following perinatal exposure to thimerosal in rats. PG - 277-83 AB - Mammalian brain development is regulated by the action of thyroid hormone (TH) on target genes. We have previously shown that the perinatal exposure to thimerosal (TM, metabolized to ethylmercury) exerts neurotoxic effects on the developing cerebellum and is associated with a decrease in cerebellar D2 activity, which could result in local brain T3 deficiency. We have also begun to examine TM effect on gene expression. The objective of this study was to expand on our initial observation of altered cerebellar gene expression following perinatal TM exposure and to examine additional genes that include both TH-dependent as well as other genes critical for cerebellar development in male and female neonates exposed perinatally (G10-G15 and P5 to P10) to TM. We report here for the first time that expression of suppressor-of-white-apricot-1 (SWAP-1), a gene negatively regulated by T3, was increased in TM-exposed males (61.1% increase), but not in females; (p<0.05). Positively regulated T3-target genes, Purkinje cell protein 2 (Pcp2; p=0.07) and Forkhead box protein P4 (FoxP4; p=0.08), showed a trend towards decreased expression in TM-exposed males. The expression of deiodinase 2 (DIO2) showed a trend towards an increase in TM-exposed females, while deiodinase 3 (DIO3), transthyretin (TTR), brain derived neurotrophic factor (BDNF) and reelin (RELN) was not significantly altered in either sex. Since regulation of gene splicing is vital to neuronal proliferation and differentiation, altered expression of SWAP-1 may exert wide ranging effects on multiple genes involved in the regulation of cerebellar development. We have previously identified activation of another TH-dependent gene, outer dense fiber of sperm tails 4, in the TM exposed male pups. Together, these results also show sex-dependent differences between the toxic impacts of TM in males and females. Interestingly, the genes that were activated by TM are negatively regulated by TH, supporting our hypothesis of local brain hypothyroidism being induced by TM and suggesting a novel mechanism of action TM in the developing brain. FAU - Khan, A AU - Khan A AD - Department of Psychiatry, Harvard Medical School/BWH, Boston, MA 02115, USA. FAU - Sulkowski, Z L AU - Sulkowski ZL FAU - Chen, T AU - Chen T FAU - Zavacki, A M AU - Zavacki AM FAU - Sajdel-Sulkowska, E M AU - Sajdel-Sulkowska EM LA - eng GR - DK76117/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - Poland TA - J Physiol Pharmacol JT - Journal of physiology and pharmacology : an official journal of the Polish Physiological Society JID - 9114501 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cell Adhesion Molecules, Neuronal) RN - 0 (Extracellular Matrix Proteins) RN - 0 (Forkhead Transcription Factors) RN - 0 (Heat-Shock Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (Odf1 protein, rat) RN - 0 (Pcp2 protein, rat) RN - 0 (Prealbumin) RN - 0 (Reelin Protein) RN - 0 (Reln protein, rat) RN - 0 (Thyroid Hormones) RN - 2225PI3MOV (Thimerosal) RN - EC 1.11.1.8 (Iodide Peroxidase) RN - EC 3.4.21.- (Serine Endopeptidases) SB - IM MH - Animals MH - Animals, Newborn/genetics/growth & development/metabolism MH - Brain-Derived Neurotrophic Factor/genetics/metabolism MH - Cell Adhesion Molecules, Neuronal/genetics/metabolism MH - Cell Differentiation/drug effects/genetics MH - Cell Proliferation/drug effects MH - Cerebellum/*drug effects/*growth & development/metabolism MH - Extracellular Matrix Proteins/genetics/metabolism MH - Female MH - Forkhead Transcription Factors/genetics/metabolism MH - Gene Expression Regulation, Developmental/*drug effects/*genetics MH - Heat-Shock Proteins/genetics/metabolism MH - Iodide Peroxidase/genetics/metabolism MH - Male MH - Nerve Tissue Proteins/genetics/metabolism MH - Neurons/drug effects/metabolism MH - Prealbumin/genetics/metabolism MH - Rats MH - Rats, Inbred SHR/genetics/metabolism MH - Reelin Protein MH - Serine Endopeptidases/genetics/metabolism MH - Sex Factors MH - Thimerosal/*pharmacology MH - Thyroid Hormones/genetics/*metabolism EDAT- 2012/07/14 06:00 MHDA- 2013/02/14 06:00 CRDT- 2012/07/14 06:00 PHST- 2012/02/15 00:00 [received] PHST- 2012/06/06 00:00 [accepted] PHST- 2012/07/14 06:00 [entrez] PHST- 2012/07/14 06:00 [pubmed] PHST- 2013/02/14 06:00 [medline] PST - ppublish SO - J Physiol Pharmacol. 2012 Jun;63(3):277-83.