Lactational exposure to low levels of the six indicator non-dioxin-like polychlorinated biphenyls induces DNA damage and repression of neuronal activity, in juvenile male mice

Toxicology. 2015 Feb 3;328:57-65. doi: 10.1016/j.tox.2014.12.011. Epub 2014 Dec 12.

Abstract

Previously, we evaluated the effects of lactational exposure to a representative mixture of the six indicator non-dioxin-like polychlorinated biphenyls (∑6 NDL-PCBs) at low levels on the neurobiological changes and developmental/behavioral performances in mice. In this study, we analyzed the global gene expression profile in cerebellar neurons isolated from male mice presenting the most significant induction of anxiety-like behavior in our previous study (10 ng/kg ∑6 NDL-PCBs). Our results revealed changes in the expression of 16658 genes in the neurons of the exposed mice. Among these, 693 upregulated [fold change (FC)>2; p<0.05] and 665 downregulated (FC<2; p<0.05) genes were statistically linked to gene ontology terms (GO). Overexpressed genes belonged to GO terms involved with the cell cycle, DNA replication, cell cycle checkpoint, response to DNA damage stimulus, regulation of RNA biosynthetic processes, and microtubule cytoskeleton organization. Downregulated genes belonged to terms involved with the transmission of nerve impulses, projection neurons, synapse hands, cell junctions, and regulation of RNA biosynthetic processes. Using qPCR, we quantified gene expression related to DNA damage and validated the transcriptomic study, as a significant overexpression of Atm-Atr Bard1, Brca2, Fancd2, Figf, Mycn, p53 and Rad51 was observed between groups (p<0.001). Finally, using immunoblots we determined the expression level of six selected proteins. We found that changes in the protein expression of Atm Brca1, p53, Kcnma1, Npy4r and Scn1a was significant between exposed and control groups (p<0.05), indicating that the expression pattern of these proteins agreed with the expression pattern of their genes by qPCR, further validating our transcriptomic findings. In conclusion, our study showed that early life exposure of male mice to a low level of ∑6 NDL-PCBs induced p53-dependent responses to cellular stress and a decrease in the expression of proteins involved in the generation, conduction, and transmission of electrical signals in neurons.

Keywords: Cerebellum; Early exposure; Indicator non-dioxin-like polychlorinated biphenyls; Neuron; Stress; Transcriptomics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Blotting, Western
  • Cerebellum / drug effects*
  • Cerebellum / growth & development
  • Cerebellum / metabolism
  • DNA Damage*
  • Female
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Regulatory Networks / drug effects
  • Genetic Markers
  • Lactation*
  • Male
  • Maternal Exposure / adverse effects*
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neural Conduction / drug effects
  • Neural Conduction / genetics
  • Neurons / drug effects*
  • Neurons / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Polychlorinated Biphenyls / toxicity*
  • Pregnancy
  • RNA, Messenger / metabolism
  • Real-Time Polymerase Chain Reaction
  • Sex Factors
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / genetics

Substances

  • Genetic Markers
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Polychlorinated Biphenyls