Maternal thimerosal exposure results in aberrant cerebellar oxidative stress, thyroid hormone metabolism, and motor behavior in rat pups; sex- and strain-dependent effects.
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.
Department of Psychiatry, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
Z L
ZL
Sulkowski
T
T
Chen
S
S
Midha
A M
AM
Zavacki
Elizabeth M
EM
Sajdel-Sulkowska
D000818:Animals; D000831:Animals, Newborn; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007453:Iodide Peroxidase / Q000378:metabolism; D007858:Learning / Q000502:physiology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D009048:Motor Skills / Q000187:drug effects; D009420:Nervous System / Q000254:growth & development; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D011247:Pregnancy; D011310:Preservatives, Pharmaceutical / Q000633:toxicity*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D013045:Species Specificity; D013234:Stem Cells / Q000187:drug effects; D013849:Thimerosal / Q000633:toxicity*; D013963:Thyroid Hormones / Q000378:metabolism*; D014284:Triiodothyronine / Q000097:blood; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D011310:Preservatives, Pharmaceutical; D013963:Thyroid Hormones; D014284:Triiodothyronine; D013849:Thimerosal; C002744:3-nitrotyrosine; D014443:Tyrosine; D007453:Iodide Peroxidase