posted on 2022-12-29, 19:04authored bySusana Barros, Nélson Alves, Marlene Pinheiro, Marta Ribeiro, Hugo Morais, Rosa Montes, Rosario Rodil, José Benito Quintana, Ana M. Coimbra, Miguel M. Santos, Teresa Neuparth
The antidiabetic drug Metformin (MET), one of the most
prevalent
pharmaceuticals in the environment, is currently detected in surface
waters in the range of ng/L to low μg/L. As current knowledge
regarding the long-term effects of environmentally relevant concentrations
of MET in nontarget organisms is limited, the present study aimed
at investigating the generational effects of MET, in concentrations
ranging from 390 to 14 423 ng/L in the model organism Danio
rerio (up to 9 mpf), including the effects on its nonexposed
offspring (until 60 dpf). We integrate several apical end points,
i.e., embryonic development, survival, growth, and reproduction, with
qRT-PCR and RNA-seq analyses to provide additional insights into the
mode of action of MET. Reproductive-related parameters in the first
generation were particularly sensitive to MET. MET parental exposure
impacted critical molecular processes involved in the metabolism of
zebrafish males, which in turn affected steroid hormone biosynthesis
and upregulated male vtg1 expression by 99.78- to
155.47-fold at 390 and 14 432 MET treatment, respectively, pointing
to an estrogenic effect. These findings can potentially explain the
significant decrease in the fertilization rate and the increase of
unactivated eggs. Nonexposed offspring was also affected by parental
MET exposure, impacting its survival and growth. Altogether, these
results suggest that MET, at environmentally relevant concentrations,
severely affects several biological processes in zebrafish, supporting
the urgent need to revise the proposed Predicted No-Effect Concentration
(PNEC) and the Environmental Quality Standard (EQS) for MET.