Original Paper

The Cerebellum

, Volume 11, Issue 2, pp 575-586

First online:

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. SulkowskiAffiliated withDepartment of Psychiatry, Harvard Medical School and Brigham and Women’s Hospital
  • , T. ChenAffiliated withThyroid Section, Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Harvard Medical School and Brigham and Women’s Hospital
  • , S. MidhaAffiliated withDepartment of Psychiatry, Harvard Medical School and Brigham and Women’s Hospital
  • , A. M. ZavackiAffiliated withThyroid Section, Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Harvard Medical School and Brigham and Women’s Hospital
  • , Elizabeth M. Sajdel-SulkowskaAffiliated withDepartment of Psychiatry, Harvard Medical School and Brigham and Women’s HospitalDepartment of Psychiatry BWH, Harvard Institute of Medicine Email author 

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Abstract

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.

Keywords

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