0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

Sezione III: Attività per progetti
However, all the abovementioned studies refer to frankly toxic effects of
Hg, while, to our knowledge, none of them, for the foreseeable difficulties in
study design/analysis, tested the effects of sub-threshold doses of MeHg in
sub-populations with potentially increased susceptibility to neurotoxic
insult. The occurrence of Hg intoxication in pregnant/lactating mothers has
been claimed to be involved in cognitive and behavioural effects in offspring
by several epidemiological studies [see for instance Trasande et al. 2005;
2006]. In recent years, a prenatal exposure to Hg has been considered as a
potential important co-factor in autism pathogenesis. Epidemiological data
[Palmer et al. 2008] as well as re-evaluation of the results of large cohort studies
[Desoto and Hitlan 2007; Ip et al. 2004] gave more than just a hint for the
existence of such a pathogenetic link. Thus, nowadays, early exposure to Hg is
considered to play a potential significant role in the pathogenesis of autism at
least in some sub-populations of patients [see for instance Bello 2007].
However, as expected, studies in humans are far from being fully informative
in clarifying the existence of such a link. In fact, for instance, such studies
would need prolonged prospective observation in which the precise exposure
to MeHg in the mother can be ascertained, and should be focussed on a
population of women in which other environmental additional confounding
factors can be controlled or, at least, clearly defined.
The effect of perinatal MeHg administration in rodents has been evaluated
in several experimental studies. Most of them were aimed at disclosing
behavioral effects in pups or adult rodents after perinatal exposure, rather
than at investigating the occurrence of frankly neurotoxic effects, which
makes quite difficult to precisely define a dose-response curve for MeHg concerning
neurotoxicity.
For instance recently Sakamoto et al. [2002] treated chronically female
rats before, during and right after pregnancy with a sub-toxic dose of MeHg,
which does not induce toxic effects in the mother, and found cerebellar alterations
(i.e. clustered losses of PCs, and heterotopic locations of granule and
PCs) in the offspring. Furthermore, different species and strains of rodents
have been used in the different studies. In particular, both rats [see, for
instance, Roegge et al. 2006; Rossi et al. 1997; Rasmussen et al. 2001; Coccini
et al. 2007] and mice [Watanabe et al. 1999; Stringari et al. 2008; Goulet et al.
2003; Markowski et al. 1998; Doré et al. 2001; Franco et al. 2006] have been
used, and oral administration (in most of studies) or s.c. or i.p. administration
of MeHg have been tested. Concerning the time length of MeHg administration
to the dams, as already mentioned MeHg easily crosses the placental barrier,
it is present also in mother milk and easily crosses the gastro-intestinal
barrier [see Clarkson 2002]. Most perinatal exposure studies investigated the
effects of administration from gestational day 0 throughout delivery and lactation
period, up to weaning or slightly earlier.
Reelin is a large secreted protein that is critical for neuron positioning
during brain development [D’Arcangelo et al. 1995; Tissir, Goffinet 2003].
Reelin is produced by marginal zone Cajal−Retzius cells and by cerebellar
granule cells. In the adult, Reelin is synthesized by GABAergic interneurons in
cortex, hippocampus, and olfactory bulb and glutamatergic cerebellar granule
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