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Effetti di miscele di contaminati alimentari su target putativi di esposizione a interferenti endocrini : un approccio biomarker-tossicogenomico
No full textThe Endocrine Disruptors (EDs) are a class of chemicals that may interfere
with the endocrine system that plays a crucial role in maintaining the
physiological homeostasis of the human body as well as in regulating body
growth, metabolism, reproduction and behavior (Faroon et al., 2001; Schell
and Gallo, 2010). The EDs can exert their effects through a number of
different mechanisms in particular interacting with nuclear (NRs) and
orphan receptors, enzymatic pathways involved in steroid biosynthesis and
detoxification metabolism (Diamanti-Kandarakis, 2009).
Polychlorinated biphenyls (PCBs) form a group of fat soluble and
environmentally persistent EDs able to bioaccumulate in lipid fraction of
animal tissue leading to biomagnification in the food chain. PCBs intake via
food of animal origin represents the main route of human exposure (EFSA,
2010).
PCBs can be divided into two groups according to their biochemical and
toxicological properties: Dioxin-like (DL) PCBs, mainly interacting with
the Aryl Hydrocarbon Receptor (AhR) and Non Dioxin-like (NDL) PCBs
whose mechanisms of action are not fully clarified. Actually, organisms are
exposed to several congeners at the same time and, accordingly, the
observed toxicological effects, such as on liver, thyroid, immune function,
reproduction and behavior as well as carcinogenicity (EFSA, 2005), are
exerted by mixtures. Therefore, new researches are required to study EDs
mixtures, in particular on possible additive/synergistic effects at “real-life”
dose levels.
In this study, 21 environmentally relevant PCB congeners were divided in
three groups according to the proposed classification of Wolff et al. (1997)
and Negri et al. (2003), based on structural and modes of action similarities:
Mix1 (PCB 44, 49, 52, 101, 174, 177, 187, 201), potentially estrogenic
NDL congeners, Mix2 (PCB 77, 81, 105, 114, 118, 126, 169) featuring DLPCB
and Mix3 (PCB 99, 153, 180, 183, 196, 203), NDL-PCBs highly
persistent in the organism and phenobarbital-like inducers of Cytochrome
P450 (CYP450).
The aim of the present project was to evaluate potential effects on liver and
on adipose tissue as target organs of PCBs, elicited by the mixtures, at
realistic human exposure levels, as derived from human exposure data
through the evaluation of biomarkers response.
Two in vitro models have been selected as representative of liver tissue and
corresponding to two different life stages: infant (HuH6) and pubertal
(HepG2) cells.
To evaluate synergic effect, biomarkers of effect were used as indicators to
measure PCB-induced variation in cellular or biochemical processes (NRs,
NRF2, CYP450 enzymes and markers of oxidative stress). Moreover gene
expression profiles of PCBs treated HepG2 cell line were evaluated by
microarray analysis.
Moreover, PCBs bioaccumulation and permanence in animal fat could
affect preadipocyte programming and differentiation and adipocytes
metabolism. Therefore, differentiation of mouse (3T3-L1) and human
preadipocytes (SGBS cells) was evaluated to determine the effect of PCBs
exposure. Moreover gene expression of biomarkers involved in adipocytes
differentiation and metabolism were analyzed in 3T3-L1.
Previous reports classified Mix1 as potentially antiandrogenic congeners
(Wolff et al., 1995), on the contrary, we observed in HepG2 cell line, that
Mix1 significantly up-regulated only AR suggesting a potential androgenic
effect. In HepG2 cells, we also observed an uncoupling in ROS-CYP1A1
regulation and in HuH6, GSH/GSSG ratio was significantly higher. As for
Gene Ontology enrichment analysis, Mix1-modulated gene list was
uniquely significant for terms related to Nuclear Transport and significantly
affected only one pathway, the Intestinal Immune Network for IgA
production, implying a stimulation of the immune response. Overall, these
molecular processes may be considered specific markers of Mix1 effect in
hepatic cells.
As regards effects on adipocytes, Mix1 increased SGBS differentiation at
3x concentration and in 3T3-L1 affected only C/EBP involved in adipose
tissue development.
Mix2, featuring DL-PCB congeners, exerted the up-regulation of AR and
AhR in HepG2 cells. Moreover, Mix2 increased ROS levels as well as
CYP1A1 mRNA expression both mediated by AhR (Kopf et al., 2010).
However Mix2 significantly decreased the CYP1A1 enzyme activity,
indicating a different effect possibly due to the low concentrations used.
In HuH6, Mix2 induced a down regulation of CAR mRNA expression that
may explain the reduction of CYP1A1 and CYP3A4 activity. Therefore,
CAR gene expression and CYP1A1 and CYP3A4 activities may be
assumed as target of DL-PCBs disruption on this hepatic cell line.
Microarray results evidenced Mix2 affected genes involved in RNA
processing and splicing, protein localization and catabolism and
macromolecules degradation. Noteworthy, main and characteristic effects of
Mix2 relied a) on enrichment of genes related several cancer pathways as
p53, activator of genes involved also in cell cycle arrest (Lanni and Jacks,
1998), apoptosis and in communication in adjacent cells, and b) on cell
cycle progression, inducing of G1 phase and inhibiting S phase. So we may
hypothesize that a sum of contrasting mode of action exerted by PCB
congeners in Mix2 occurred.
As regards effects on adipocytes, Mix2 significantly induced SGBS
differentiation only at 3x concentration, probably due to the mixture effect
and/or the lower concentration levels used in this study.
Mix3 treatment affected the wider number of NRs expression (ER , ER ,
AR, PXR, RAR , THR ) as well as NRF2, in particular, in HuH6. To our
knowledge, it is the first study that showed AR mRNA expression due to
PCB congeners included in Mix3, whereas the observed ER and ER
induction confirmed the estrogenic effect of PCB 99 and 153 (Warner et al,
2012).The decrease in the CYP3A4 enzyme activity in HuH6 cells was in
agreement with NRF2 gene expression down-regulation (Itoh et al, 1997).
Microarray analysis showed that Mix3 modulated the higher number of
genes (5979 genes) with 1501 shared with Mix2-affected genes. Apart some
GO enriched terms related to cell organization, Mix3 did not share other
effects with Mix1, the other NDL mixture.
One of the most interesting evidence is the enrichment of genes involved in
the Wnt signaling pathway by only Mix3, suggesting an unbalance toward
pluripotency promotion (Takemarua and Moona, 2000).
Mix3 also affected some cancer pathways as well as the adherens junction
pathway as Mix2 but modulating a different panel of involved genes.
Moreover Mix3 exerted the higher magnitude of effect on pre-adipocytes
differentiation in both murine and human cell lines. Gene expression
evaluation analysis outlined that Mix3 down regulated Hes1, a DNA
binding protein whose expression blocks adipogenesis (Ross et al., 2006).
Overall results confirmed that the adopted grouping of PCBs in three
mixtures served to highlight different modes of action as well as biomarkers
responses, also among mixtures featuring NDL congeners. Moreover, the
two hepatic cell lines and the two pre-adipocytes cell lines appear to be
differently reactive to PCBs, indicating the need to use different in vitro
models and a panel of biomarkers in order to characterize the EDs effects.
These represented new results since there are no studies on PCB mixtures
summarizing effects on oxidative stress, metabolism, nuclear receptors gene
expression and adipocytes differentiation responses following treatment at
human real exposure concentrations.
As prompted by EFSA (2005), it is necessary to provide evidences
concerning comprehensive toxicological end-points of NDL effects.
Therefore, these data may serve as a basis for developing relative
toxicological factors for the NDL congeners risk assessment
Chaos/Kosmos
No full textIn questo numero la contraddizione, o meglio la contrarietà come osserva giustamente la curatrice Francesca Gambetti, si manifesta già nel titolo riproponendo appunto una dualità che si può definire classica e pertanto offre un ricco patrimonio di indagini, una molteplicità e pluralità di fili – ora aggrovigliati, ora più lineari –, dipanati da autori e autrici con passione e competenza, con l’intento di incidere su rigidità precostituite, tentando di rispondere alle esigenze diffuse di un ripensamento dei saperi.
La polarità del titolo rinvia in realtà a una pluralità di ambiti: dai miti antichi alla loro rielaborazione in Parmenide, dalla scienza fisica alle filosofia del linguaggio, dalle antinomie kantiane alla contrapposizione analitici e continentali, dall’ antropologia al pensiero politico contemporaneo, fino alla musica, che para10
dossalmente può esprimere il chaos come cifra del kosmos. Il quadro che risulta, seppure non esaustivo, disegna una mappa molto articolata di un «chaos deterministicamente ordinato»
Kafaalo Magazine
No full textKafaalo Magazine is primarily designed to serve as an overview on research for Somalis worldwide, to keep them informed on their economical and social issues. It is well known in different countries with analytical results and recommendations. The KM is also an educational, scientific and innovation magazine aiming to enhance professional and educational aspirations amongst Somalis. It promotes ideas and experiences from the work of educational professionals, as well as from academic journals and business innovations.Kafaalo Magazine waa majallad sannadeed oo xubin rasmi ah ay ka tahay Kafaalo Academy, oo ah iskuullo Soomaaliyeed oo lagu taageero kobcinta aqoonta, waxayna majalladu ka soo baxdaa dalka Norway. Mawaadiicdeedu ugu doorka rooni waxay ka hadlayaana: saynis, tarbiyad, waxbarasho, arrimaha bulshada, taariikhda, diinta iyo dhaqaalaha oo waxtar weyn u leh bulshada Soomaaliyeed. Majaladdan waxaa loogu talaggalay dadka akhriya af Soomaaliga, wuxuuna ka hadlaa mawduucyo wada taabanaya qofka noloshiisa, haddana kobcinaya qaab fekerkiisa iyo aqoontiisa.Kafaalo Magazine è destinato principalmente a fornire una visione d'insieme sulla ricerca per i somali in tutto il mondo, al fine di tenere aggiornati gli utenti sugli aspetti economici e sociali. E' conosciuta in diversi paesi come testimoniano risultati analitici e raccomandazioni. Il KM è anche una rivista educativa, scientifica e sull'innovazione che ha lo scopo di stimolare aspirazioni formative e professionali tra i somali. Promuove idee ed esperienze dal lavoro dei professionisti, così come da riviste accademiche e innovazioni aziendali
Faafinta Rasmiga ah ee Jamhuuriyadda Soomaaliya [Janaayo - Disembar 2013]
No full textUrurinta Faafinta Rasmiga ah ee Jamhuuriyadda Soomaaliyeed ee la soo saaray sannadka 2013.Raccolta delle Gazzette Ufficiali della Repubblica Somala relative al 2013.Collection of the Official Bulletins of Somali Republic published in 2013.Qareen Cabdullaahi Darmaan ayaa dokumentigan ku deeqay xarunta cilmibaarista (Centro Studi Somali).Documento messo a disposizione del Centro Studi Somali dall'Avv. Abdullahi Darman.Document provided to the Somali Studies Centre by lawyer Abdullahi Darman
