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Centro Mandela DD. HH.”
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Glyphosate-Based Herbicides Produce Teratogenic Effects on Vertebrates by Impairing Retinoic Acid Signaling

Los herbicidas a base de glifosato producen efectos teratogénicos en los vertebrados y afectar a señalización de ácido retinoico.
Alejandra Paganelli, Victoria Gnazzo, Helena Acosta, Silvia L. Lopez and Andres E. Carrasco*

Laboratorio de Embriología Molecular, CONICET-UBA, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 3° piso (1121), Ciudad Autónoma de Buenos Aires, Argentina

Chem. Res. Toxicol., Article ASAP

DOI: 10.1021/tx1001749

Publication Date (Web): August 9, 2010

Copyright © 2010 American Chemical Society

* Corresponding author. Phone: +5411 5950 9500 ext. 2216. Fax: +5411 5950 9626. E-mail: acarrasco@fmed.uba.ar.

Fuente (Source):
http://pubs.acs.org/doi/abs/10.1021/tx1001749

Abstract Resumen


The broad spectrum herbicide glyphosate is widely used in agriculture worldwide. There has been ongoing controversy regarding the possible adverse effects of glyphosate on the environment and on human health. Reports of neural defects and craniofacial malformations from regions where glyphosate-based herbicides (GBH) are used led us to undertake an embryological approach to explore the effects of low doses of glyphosate in development. Xenopus laevis embryos were incubated with 1/5000 dilutions of a commercial GBH. The treated embryos were highly abnormal with marked alterations in cephalic and neural crest development and shortening of the anterior−posterior (A-P) axis. Alterations on neural crest markers were later correlated with deformities in the cranial cartilages at tadpole stages. Embryos injected with pure glyphosate showed very similar phenotypes. Moreover, GBH produced similar effects in chicken embryos, showing a gradual loss of rhombomere domains, reduction of the optic vesicles, and microcephaly. This suggests that glyphosate itself was responsible for the phenotypes observed, rather than a surfactant or other component of the commercial formulation. A reporter gene assay revealed that GBH treatment increased endogenous retinoic acid (RA) activity in Xenopus embryos and cotreatment with a RA antagonist rescued the teratogenic effects of the GBH. Therefore, we conclude that the phenotypes produced by GBH are mainly a consequence of the increase of endogenous retinoid activity. This is consistent with the decrease of Sonic hedgehog (Shh) signaling from the embryonic dorsal midline, with the inhibition of otx2 expression and with the disruption of cephalic neural crest development. The direct effect of glyphosate on early mechanisms of morphogenesis in vertebrate embryos opens concerns about the clinical findings from human offspring in populations exposed to GBH in agricultural fields.

El glifosato herbicida de amplio espectro se usa ampliamente en la agricultura mundial. There has been ongoing controversy regarding the possible adverse effects of glyphosate on the environment and on human health. Ha habido controversia en curso sobre los posibles efectos adversos del glifosato en el medio ambiente y la salud humana. Reports of neural defects and craniofacial malformations from regions where glyphosate-based herbicides (GBH) are used led us to undertake an embryological approach to explore the effects of low doses of glyphosate in development. Xenopus laevis embryos were incubated with 1/5000 dilutions of a commercial GBH. Informes de los defectos de los nervios y las malformaciones craneofaciales de las regiones donde los herbicidas basados en glifosato (GBH) se utilizan nos llevo a plantear una aproximación embriológica para explorar los efectos de bajas dosis de glifosato en el desarrollo. Xenopus laevis embriones se incubaron con 1 / 5000 diluciones de un GBH comerciales. The treated embryos were highly abnormal with marked alterations in cephalic and neural crest development and shortening of the anterior−posterior (AP) axis. Los embriones tratados fueron altamente anormal con marcadas alteraciones en desarrollo de la cresta neural cefálica y limitación del anterior-posterior (AP) eje. Alterations on neural crest markers were later correlated with deformities in the cranial cartilages at tadpole stages. Las alteraciones en los marcadores cresta neural fueron relacionados posteriormente con deformidades craneales en los cartílagos en las fases de renacuajo. Embryos injected with pure glyphosate showed very similar phenotypes. Los embriones inyectados con glifosato puro mostraron fenotipos muy similares. Moreover, GBH produced similar effects in chicken embryos, showing a gradual loss of rhombomere domains, reduction of the optic vesicles, and microcephaly. Por otra parte, GBH producido efectos similares en los embriones de pollo, mostrando una pérdida gradual de dominios rhombomere, la reducción de las vesículas ópticas, y microcefalia. This suggests that glyphosate itself was responsible for the phenotypes observed, rather than a surfactant or other component of the commercial formulation. Esto sugiere que el glifosato sí era responsable de los fenotipos observados, en lugar de un componente surfactante u otro de la formulación comercial. A reporter gene assay revealed that GBH treatment increased endogenous retinoic acid (RA) activity in Xenopus embryos and cotreatment with a RA antagonist rescued the teratogenic effects of the GBH. Un ensayo de gen reveló que el tratamiento GBH aumento del ácido retinoico endógeno (AR) la actividad en embriones de Xenopus y cotratamiento con un antagonista de la AR rescató a los efectos teratogénicos de la GBH. Therefore, we conclude that the phenotypes produced by GBH are mainly a consequence of the increase of endogenous retinoid activity. Por lo tanto, concluimos que los fenotipos producidos por GBH son principalmente consecuencia del aumento de la actividad retinoide endógeno. This is consistent with the decrease of Sonic hedgehog (Shh) signaling from the embryonic dorsal midline, with the inhibition of otx2 expression and with the disruption of cephalic neural crest development. Esto es consistente con la disminución de sonic hedgehog (Shh) de señalización de la línea media dorsal de embriones, con la inhibición de la expresión y OTX2 con la interrupción del desarrollo de la cresta neural cefálica. The direct effect of glyphosate on early mechanisms of morphogenesis in vertebrate embryos opens concerns about the clinical findings from human offspring in populations exposed to GBH in agricultural fields. El efecto directo del glifosato sobre los mecanismos iníciales de la morfogénesis en embriones de vertebrados abre las preocupaciones sobre los resultados clínicos de embriones humanos en las poblaciones expuestas a GBH en los campos agrícolas.

Fuente (Source): http://pubs.acs.org/doi/abs/10.1021/tx1001749

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