On the origin of Robertsonian fusions in nature: evidence of telomere shortening in wild house mice.

The role of telomere shortening to explain the occurrence of Robertsonian (Rb) fusions, as well as the importance of the average telomere length vs. the proportion of short telomeres, especially in nature populations, is largely unexplored. In this study, we have analysed telomere shortening in nine wild house mice from the Barcelona Rb system with diploid numbers ranging from 29 to 40 chromosomes. We also included two standard (2n=40) laboratory mice for comparison. Our data showed that the average telomere length (considering all chromosomal arms) is influenced by both the diploid number and the origin of the mice (wild vs. laboratory). In detail, we detected that wild mice from the Rb Barcelona system (fused and standard) present shorter telomeres than standard laboratory mice. However, only wild mice with Rb fusions showed a high proportion of short telomeres (only in p-arms), thus revealing the importance of telomere shortening in the origin of the Rb fusions in the Barcelona system. Overall, our study confirms that the number of critically short telomeres, and not a simple reduction in the average telomere length, is more likely to lead to the origin of Rb fusions in the Barcelona system and ultimately in nature.

Gene expression is altered after bisphenol A exposure in human fetal oocytes in vitro.

Bisphenol A (BPA) is a 'weak' endocrine disruptor. The effect of BPA on human reproduction is controversial but has been related to meiotic anomalies, recurrent spontaneous abortion, abnormal karyotypes, the diminishing of oocyte survival, delay in meiotic progression and an elevated rate of MLH1 foci in vitro. The aim of this study is to characterize the gene expression of human fetal oocytes in culture as well as to evaluate the effect of BPA in cultured human oocytes. To accomplish our objective, 12 ovaries from 6 euploid fetuses were used. The ovarian fetal tissue was cultivated in two groups: control group and BPA group (BPA30 µM). The cultures were analyzed at T0 and after 7 (T7), 14 (T14) and 21 (T21) days of culture. Evaluation of gene expression was performed by real-time PCR (RT-PCR), with the evaluated genes being: Smc1ß, Sycp1 (pairing-synapsis), Spo11, Rpa, H2ax, Mlh1 and Blm [double-strand break (DSBs) generation, signaling and repair], Erα, Erß and Errγ (estrogen receptors), Stra8 and Nalp5 (markers of meiotic progression). Oocytes from ovaries cultured and treated with BPA show changes in the expression of Spo11, H2ax and Blm genes, with a significant increase from 3- to 5-fold (P≤ 0.05). Finally, Rpa, showed a 100-fold increment (P≤ 0.01). Erα, Erß and Errγ genes showed a BPA up-regulation of 2-4-fold in all of the culture times (P≤ 0.05). Oocytes exposed to BPA showed an up-regulation of genes involved in DSB generation, signaling and repair except by Mlh1. Thus, BPA can modify the gene expression pattern, which may explain the effects of BPA on female germ cells.

Δ9-tetrahydrocannabinol modulates the proteasome system in the brain.

Cannabis is the most consumed illicit drug worldwide. Its principal psychoactive component, Δ9-tetrahydrocannabinol (THC), affects multiple brain functions, including cognitive performance, by modulating cannabinoid type-1 (CB1) receptors. These receptors are strongly enriched in presynaptic terminals, where they modulate neurotransmitter release. We analyzed, through a proteomic screening of hippocampal synaptosomal fractions, those proteins and pathways modulated 3 h after a single administration of an amnesic dose of THC (10 mg/kg, i.p.). Using an isobaric labeling approach, we identified 2040 proteins, 1911 of them previously reported in synaptic proteomes, confirming the synaptic content enrichment of the samples. Initial analysis revealed a significant alteration of 122 proteins, where 42 increased and 80 decreased their expression. Gene set enrichment analysis indicated an over-representation of mitochondrial associated functions and cellular metabolic processes. A second analysis focusing on extreme changes revealed 28 proteins with altered expression after THC treatment, 15 of them up-regulated and 13 down-regulated. Using a network topology-based scoring algorithm we identified those proteins in the mouse proteome with the greatest association to the 28 modulated proteins. This analysis pinpointed a significant alteration of the proteasome function, since top scoring proteins were related to the proteasome system (PS), a protein complex involved in ATP-dependent protein degradation. In this regard, we observed that THC decreases 20S proteasome chymotrypsin-like protease activity in the hippocampus. Our data describe for the first time the modulation of the PS in the hippocampus following THC administration under amnesic conditions that may contribute to an aberrant plasticity at synapses.