Browsing by Issue Date, starting with "2014-04-03"
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- Syndromes associated with mitochondrial DNA depletionPublication . Nogueira, Célia; Almeida, Ligia S.; Nesti, C.; Pezzini, I.; Videira, A.; Vilarinh, Laura; Santorelli, F.M.Mitochondrial dysfunction accounts for a large group of inherited metabolic disorders most of which are due to a dysfunctional mitochondrial respiratory chain (MRC) and, consequently, deficient energy production. MRC function depends on the coordinated expression of both nuclear (nDNA) and mitochondrial (mtDNA) genomes. Thus, mitochondrial diseases can be caused by genetic defects in either the mitochondrial or the nuclear genome, or in the cross-talk between the two. This impaired cross-talk gives rise to so-called nuclear-mitochondrial intergenomic communication disorders, which result in loss or instability of the mitochondrial genome and, in turn, impaired maintenance of qualitative and quantitative mtDNA integrity. In children, most MRC disorders are associated with nuclear gene defects rather than alterations in the mtDNA itself.The mitochondrial DNA depletion syndromes (MDSs) are a clinically heterogeneous group of disorders with an autosomal recessive pattern of transmission that have onset in infancy or early childhood and are characterized by a reduced number of copies of mtDNA in affected tissues and organs. The MDSs can be divided into least four clinical presentations: hepatocerebral, myopathic, encephalomyopathic and neurogastrointestinal. The focus of this review is to offer an overview of these syndromes, listing the clinical phenotypes, together with their relative frequency, mutational spectrum, and possible insights for improving diagnostic strategies.
- Are standard genotoxicity tests useful for the safety evaluation of nanomaterials?Publication . Louro, Henriqueta; Tavares, Ana; Vital, Nádia; Antunes, Susana; Costa, Pedro; Alverca, Elsa; Lavinha, João; Silva, Maria JoãoNanomaterials (NMs) are widely used in a diversity of consumer products, despite uncertainties surrounding the potential health risks that they pose to humans and the environment. One of the major concerns is the potential to induce cancer. To analyze in a short term the carcinogenic properties of a compound, genotoxicity assays in mammalian cell lines or animal models are frequently used. In the context of an EU Joint Action, in the present work we have used standard genotoxicity assays (comet, micronucleus and mutation assays) to investigate the effects associated with the exposure to titanium dioxide nanomaterials (TiO2), following standardized dispersion and assay procedures, in three types of human cells and in a mouse model. The results showed slight but significant increases in the frequencies of micronuclei after exposure to some of the NMs, as compared to controls. No clear dose-response relationships could be disclosed. One of the tested TiO2 yielded equivocal results in vitro micronucleus assay and was positive in the comet assay in pulmonary cells. In view of the inconclusive results,it was further analyzed in vivo, using the lacZ transgenic mouse model. It did not induce genotoxic effects in mice, 28 days after injection, despite the accumulation of the NM observed in the mouse liver. Regarding safety assessment, the different genotoxicity observed for closely related NMs, but that differ in some physicochemical characteristics, highlights the importance of investigating the toxic potential of each NM individually, instead of assuming a common mechanism and equal genotoxic effects for a set of similar NMs. The equivocal genotoxicity of the nanosized TiO2 in human cells in vitro was not confirmed in vivo, and therefore the predictive value of these in vitro tests for identifying genotoxic (and potentially carcinogenic) NMs in vivo should be clarified, before extrapolating the conclusions for human health.
- Genotoxicity testing towards a knowledge-based regulation of nanomaterialsPublication . Silva, Maria João; Louro, Henriqueta; Lavinha, JoãoNanotechnologies are developing very rapidly and the exploitation of manufactured nanomaterials (MNMs) is gaining ascendancy in science, industry and biomedicine. However, comparatively less research has been performed to guarantee their safety for humans and the environment. In the context of risk assessment, solid information about human exposure and hazard is lacking for the vast majority of MNMs, especially related to chronic exposure to low doses that is likely to occur, e.g., in occupational settings or through consumer products. Focusing on hazard characterization, the genotoxic effects of MNMs, which may be linked to carcinogenic effects, are of special concern because cancer has a long latency period and these late effects can be less obvious and more difficult to predict than the acute effects. The small size, large surface area and unique surface properties of MNMs greatly influence their reactivity in biological systems and trigger some unpredictable cell responses, representing a challenge in terms of hazard assessment. In the context of NANoREG, which is intended to answer regulatory questions and requirements from regulators and legislators, the contribution of PToNANO includes the genotoxicity assessment of well characterized MNMs, using standardized and validated tests and strategies, thereby contributing to the knowledge basis for their regulation. In the future, accommodating the safety evaluation within the innovation process will stimulate the relationship between innovation and risk regulation. This is applicable to the innovation process itself as to the regulation of the resulting products and technologies, in order to promote the benefits from innovation while protecting the public health and the environment.