Long-lasting depression-like behavior and epigenetic changes of BDNF gene expression induced by perinatal exposure to methylmercury.
Substantial evidence indicates that predisposition to diseases can be acquired during early stages of development and interactions between environmental and genetic factors may be implicated in the onset of many pathological conditions. Data collected over several decades have shown that chemicals are among the relevant factors that can endanger CNS. We previously showed that perinatal exposure to methylmercury (MeHg) causes persistent changes in learning and motivational behavior in mice. In this study, we report that the depression-like behavior in MeHg-exposed male mice is reversed by chronic treatment with the antidepressant fluoxetine. Behavioral alterations are associated with a decrease in brain-derived neurotrophic factor (BDNF) mRNA in the hippocampal dentate gyrus and fluoxetine treatment restores BDNF mRNA expression. We also show that MeHg-exposure induces long-lasting repressive state of the chromatin structure at the BDNF promoter region, in particular DNA hypermethylation, an increase in histone H3-K27 tri-methylation and a decrease in H3 acetylation at the promoter IV. While fluoxetine treatment does not alter hypermethylation of H3-K27, it significantly up-regulates H3 acetylation at the BDNF promoter IV in MeHg-exposed mice. Our study shows that developmental exposure to low levels of MeHg predisposes mice to depression and induces epigenetic suppression of BDNF gene expression in the hippocampus.
Onishchenko
Natalia
N
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Karpova
Nina
N
Sabri
Farideh
F
Castrén
Eero
E
Ceccatelli
Sandra
S
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics*; D003863:Depression / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005473:Fluoxetine / Q000627:therapeutic use; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects* / Q000502:physiology; D007103:Immobilization; D008297:Male; D008767:Methylmercury Compounds / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D008767:Methylmercury Compounds; D005473:Fluoxetine