The Cerebellum

, Volume 11, Issue 2, pp 575–586 | Cite as

Maternal Thimerosal Exposure Results in Aberrant Cerebellar Oxidative Stress, Thyroid Hormone Metabolism, and Motor Behavior in Rat Pups; Sex- and Strain-Dependent Effects

  • Z. L. Sulkowski
  • T. Chen
  • S. Midha
  • A. M. Zavacki
  • Elizabeth M. Sajdel-SulkowskaEmail author
Original Paper


Methylmercury (Met-Hg) and ethylmercury (Et-Hg) are powerful toxicants with a range of harmful neurological effects in humans and animals. While Met-Hg is a recognized trigger of oxidative stress and an endocrine disruptor impacting neurodevelopment, the developmental neurotoxicity of Et-Hg, a metabolite of thimerosal (TM), has not been explored. We hypothesized that TM exposure during the perinatal period impairs central nervous system development, and specifically the cerebellum, by the mechanism involving oxidative stress. To test this, spontaneously hypertensive rats (SHR) or Sprague–Dawley (SD) rat dams were exposed to TM (200 μg/kg body weight) during pregnancy (G10–G15) and lactation (P5–P10). Male and female neonates were evaluated for auditory and motor function; cerebella were analyzed for oxidative stress and thyroid metabolism. TM exposure resulted in a delayed startle response in SD neonates and decreased motor learning in SHR male (22.6%), in SD male (29.8%), and in SD female (55.0%) neonates. TM exposure also resulted in a significant increase in cerebellar levels of the oxidative stress marker 3-nitrotyrosine in SHR female (35.1%) and SD male (14.0%) neonates. The activity of cerebellar type 2 deiodinase, responsible for local intra-brain conversion of thyroxine to the active hormone, 3′,3,5-triiodothyronine (T3), was significantly decreased in TM-exposed SHR male (60.9%) pups. This coincided with an increased (47.0%) expression of a gene negatively regulated by T3, Odf4 suggesting local intracerebellar T3 deficiency. Our data thus demonstrate a negative neurodevelopmental impact of perinatal TM exposure which appears to be both strain- and sex-dependent.


Ethylmercury Rat Cerebellum Oxidative stress marker 3-nitrotrosine (3-NT) Type 2 deiodinase (D2) 



We would like to thank the Mercury as a Global Hazard SGIG for the grant awarded by the College of William and Mary to Z.L. Sulkowski, the Autism Research Institute and SafeMinds for grants awarded to Dr. Sajdel-Sulkowska, and the NIDDK-DK76117 grant awarded to A.M. Zavacki. We would also like to thank Puja Parekh of the College of William for participating in the initial experiments and Ming Xu, Dept. Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi Gunma, Japan, for initial tissue analysis. We also acknowledge the following Sponsored Research Staff members at Brigham and Women’s Hospital: Amrutha E. Mathew, Pooja Mathew and Ashesh Shresta for RNA preparation, and Dr. Alaptagin Khan for PCR primer validation.


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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Z. L. Sulkowski
    • 1
  • T. Chen
    • 2
  • S. Midha
    • 1
  • A. M. Zavacki
    • 2
  • Elizabeth M. Sajdel-Sulkowska
    • 1
    • 3
    Email author
  1. 1.Department of PsychiatryHarvard Medical School and Brigham and Women’s HospitalBostonUSA
  2. 2.Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Department of MedicineHarvard Medical School and Brigham and Women’s HospitalBostonUSA
  3. 3.Department of Psychiatry BWHHarvard Institute of MedicineBostonUSA

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