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

Department of Psychiatry, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
The Cerebellum (Impact Factor: 2.72). 10/2011; 11(2):575-86. DOI: 10.1007/s12311-011-0319-5
Source: PubMed

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.

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    • "Evidence from animal studies demonstrates the neurodevelopmental impact of prenatal [37, 38] and perinatal exposure to vaccine-EtHg [39, 40]; these studies included infants of several species (mice, rats, and macaques) and suggest that the cumulative effects of TCV-Hg could lead to cognitive and social deficits and delayed acquisition of reflexes. Because this literature is very recent, it has not yet modeled the wide spectrum of human infant diversity and the full interaction with other neurotoxicants [41]. "
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    BioMed Research International 04/2012; 2012:132876. DOI:10.1155/2012/132876 · 2.71 Impact Factor
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    ABSTRACT: 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.
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    ABSTRACT: Mercury (Hg) exposure is ubiquitous in modern society via vaccines, fish/crustacea, dental amalgam, food, water, and the atmosphere. This paper examines Hg exposure in the context of primary exposure to pregnant women and secondary exposure experienced by their unborn babies. Babies in utero are particularly at risk of higher Hg exposure than adults (on a dose/weight basis through maternal Hg transfer via the placenta), and more susceptible to adverse effects of this metal. It is, therefore, critical that regulatory advisories around maximum safe Hg exposures account for pregnant women and secondary exposure that children in utero experience. This study focused on standardized embryonic and fetal Hg exposures via primary exposure to the pregnant mother of two common Hg sources (dietary fish and parenteral vaccines). Data demonstrated that Hg exposures, particularly during the first trimester of pregnancy, at well-established dose/weight ratios produced severe damage to humans including death. In light of research suggestive of a mercuric risk factor for childhood conditions such as tic disorders, cerebral palsy, and autism, it is essential that Hg advisories account for secondary prenatal human exposures.
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