Sex- and structure-specific differences in antioxidant responses to methylmercury during early development

Joanna A. Ruszkiewicz, Aaron B. Bowman, Marcelo Farina, João B T Rocha, Michael Aschner

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Methylmercury (MeHg) is a ubiquitous environmental contaminant and neurotoxin, particularly hazardous to developing and young individuals. MeHg neurotoxicity during early development has been shown to be sex-dependent via disturbances in redox homeostasis, a key event mediating MeHg neurotoxicity. Therefore, we investigated if MeHg-induced changes in key systems of antioxidant defense are sex-dependent. C57BL/6J mice were exposed to MeHg during the gestational and lactational periods, modeling human prenatal and neonatal exposure routes. Dams were exposed to 5 ppm MeHg via drinking water from early gestational period until postnatal day 21 (PND21). On PND21 a pair of siblings (a female and a male) from multiple (5–6) litters were euthanized and tissue samples were taken for analysis. Cytoplasmic and nuclear extracts were isolated from fresh cerebrum and cerebellum and used to determine thioredoxin (Trx) and glutathione (GSH) levels, as well as thioredoxin reductase (TrxR) and glutathione peroxidase (GPx) activities. The remaining tissue was used for mRNA analysis. MeHg-induced antioxidant response was not uniform for all the analyzed antioxidant molecules, and sexual dimorphism in response to MeHg treatment was evident for TrxR, Trx and GPx. The pattern of response, namely a decrease in males and an increase in females, may impart differential and sex-specific susceptibility to MeHg. GSH levels were unchanged in MeHg treated animals and irrespective of sex. Trx was reduced only in nuclear extracts from male cerebella, exemplifying a structure-specific response. Results from the gene expression analysis suggest posttranscriptional mechanism of sex-specific regulation of the antioxidant response upon MeHg treatment. The study demonstrates for the first time sex-and structure-specific changes in the response of the thioredoxin system to MeHg neurotoxicity and suggests that these differences in antioxidant responses might impart differential susceptibility to developmental MeHg exposure.

Original languageEnglish (US)
Pages (from-to)118-126
Number of pages9
JournalNeuroToxicology
Volume56
DOIs
StatePublished - Sep 1 2016

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Antioxidants
Thioredoxins
Thioredoxin-Disulfide Reductase
Peroxiredoxins
Glutathione Peroxidase
Cerebellum
Tissue
Neurotoxins
Gene expression
Drinking Water
Dams
Cerebrum
Glutathione
Inbred C57BL Mouse
Animals
Sex Characteristics
Oxidation-Reduction
Impurities
Homeostasis
Messenger RNA

Keywords

  • Glutathione
  • Glutathione peroxidase
  • Methylmercury
  • Sex
  • Thioredoxin
  • Thioredoxin reductase

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

Cite this

Sex- and structure-specific differences in antioxidant responses to methylmercury during early development. / Ruszkiewicz, Joanna A.; Bowman, Aaron B.; Farina, Marcelo; Rocha, João B T; Aschner, Michael.

In: NeuroToxicology, Vol. 56, 01.09.2016, p. 118-126.

Research output: Contribution to journalArticle

Ruszkiewicz, Joanna A. ; Bowman, Aaron B. ; Farina, Marcelo ; Rocha, João B T ; Aschner, Michael. / Sex- and structure-specific differences in antioxidant responses to methylmercury during early development. In: NeuroToxicology. 2016 ; Vol. 56. pp. 118-126.
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AB - Methylmercury (MeHg) is a ubiquitous environmental contaminant and neurotoxin, particularly hazardous to developing and young individuals. MeHg neurotoxicity during early development has been shown to be sex-dependent via disturbances in redox homeostasis, a key event mediating MeHg neurotoxicity. Therefore, we investigated if MeHg-induced changes in key systems of antioxidant defense are sex-dependent. C57BL/6J mice were exposed to MeHg during the gestational and lactational periods, modeling human prenatal and neonatal exposure routes. Dams were exposed to 5 ppm MeHg via drinking water from early gestational period until postnatal day 21 (PND21). On PND21 a pair of siblings (a female and a male) from multiple (5–6) litters were euthanized and tissue samples were taken for analysis. Cytoplasmic and nuclear extracts were isolated from fresh cerebrum and cerebellum and used to determine thioredoxin (Trx) and glutathione (GSH) levels, as well as thioredoxin reductase (TrxR) and glutathione peroxidase (GPx) activities. The remaining tissue was used for mRNA analysis. MeHg-induced antioxidant response was not uniform for all the analyzed antioxidant molecules, and sexual dimorphism in response to MeHg treatment was evident for TrxR, Trx and GPx. The pattern of response, namely a decrease in males and an increase in females, may impart differential and sex-specific susceptibility to MeHg. GSH levels were unchanged in MeHg treated animals and irrespective of sex. Trx was reduced only in nuclear extracts from male cerebella, exemplifying a structure-specific response. Results from the gene expression analysis suggest posttranscriptional mechanism of sex-specific regulation of the antioxidant response upon MeHg treatment. The study demonstrates for the first time sex-and structure-specific changes in the response of the thioredoxin system to MeHg neurotoxicity and suggests that these differences in antioxidant responses might impart differential susceptibility to developmental MeHg exposure.

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