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Teratogenesis by glyphosate based herbicides and other pesticides.
Relationship with the retinoic acid pathway
Andr?s Carrasco
Lab. Molecular Embryology, School of Medicine UBA, Conicet, Argentina
In South America, the incorporation of genetically modified organisms (GMO) engineered
to be resistant to pesticides changed the agricultural model into one dependent
on the massive use of agrochemicals (Teubal et al. 2005; Teubal 2009). Different
pesticides are used in response to the demands of the global consuming market to
control weeds, herbivorous arthropods, and crop diseases.
A recent study using a commercial formulation of glyphosate based herbicides (GBH)
showed that treatments with a 1 / 5000 dilution (430 !M of glyphosate) were sufficient
to induce reproducible malformations in embryos of the South African clawed frog
Xenopus laevis, a widely used vertebrate model for embryological studies (Paganelli et
al. 2010). The phenotypes observed include shortening of the trunk, cephalic reduction,
microphthalmy, cyclopia, reduction of the neural crest territory at neurula stages and
craniofacial malformations at tadpole stages. In addition GBH inhibits the anterior
expression domain of the morphogen Sonic Hedgehog (shh) and reduces the domain of
the cephalic marker otx2, prevents the subdivision of the eye field and impairs craniofacial
development. Moreover, in recent experiments with another commercial formulation
of GBH, the malformations observed before were reproduced in a dose-dependent
manner, even at dilutions of 1 / 500000, which produced developmental abnormalities in
17 % of the embryos, without lethality (unpublished results).
It is known that glyphosate penetration through the cell membrane and subsequent
intracellular action is greatly facilitated by adjuvants such as surfactants. For this
reason, the active principle was also tested by injecting frog embryos with glyphosate
alone (between 8 and 12 μM per injected cell). The calculated intracellular concentration
for glyphosate injected into embryos was 60 times lower that the glyphosate concentration
present in the 1 / 5000 dilution of the GBH which was used to culture whole
embryos. The injection of glyphosate produced similar phenotypes and changes in gene
expression, suggesting that the effects are attributable to the active principle of the
herbicide.
It is very well known that acute or chronic increase of retinoic acid (RA) levels leads to
teratogenic effects during human pregnancy and in experimental models. The characteristic
features displayed by RA embryopathy in humans include brain abnormalities such
us microcephaly, microphtalmia and impairment of hindbrain development; abnormal
external and middle ears (microtia or anotia), mandibular and midfacial underdevelopment,
and clefts palate. These craniofacial malformations can be attributed to defects in
cranial neural crest cells. An excessive cell death in regions where apoptosis normally
takes place may underlie a general mechanism for craniofacial malformations associated
to teratogens (Sulik et al. 1988, Clotman et al. 1998)...
