title: Sex- and structure-specific differences in antioxidant responses to methylmercury during early development.
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 5ppm 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.
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address: joanna.ruszkiewicz@einstein.yu.edu.
authors.forename: Joanna A
authors.initials: JA
authors.lastname: Ruszkiewicz
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Bowman
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040900 Florianópolis, SC, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Farina
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, 97105900 Santa Maria, RS, Brazil.
authors.forename: João B T
authors.initials: JBT
authors.lastname: Rocha
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address: Michael.Aschner@einstein.yu.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D005978:Glutathione / Q000235:genetics / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D008297:Male; D008767:Methylmercury Compounds / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012727:Sex Characteristics; D013880:Thioredoxin-Disulfide Reductase / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D008767:Methylmercury Compounds; D012333:RNA, Messenger; D013879:Thioredoxins; D005979:Glutathione Peroxidase; D013880:Thioredoxin-Disulfide Reductase; D005978:Glutathione; C004925:methylmercuric chloride
keywords: Glutathione; Glutathione peroxidase; Methylmercury; Sex; Thioredoxin; Thioredoxin reductase