Resumen :
La exposición al disruptor endocrino BPA, durante la gestación, conduce a
alteraciones metabólicas en la descendencia produciendo efectos adversos en
la homeostasis de glucosa y, por tanto, a un aumento del riesgo en la aparición
de enfermedades metabólicas como la diabetes mellitus tipo 2. Por otr... Ver más
Gestational exposure to BPA leads to metabolic disorders in the offspring which
may increase the risk of developing diseases like type 2 diabetes. BPA is also
known to activate different signalling pathways through activation of estrogen
receptors (ERs) which may alter gene expression and pancreatic β-cell function.
In the present work, we analyse the effects of gestational exposure to BPA on
pancreatic β-cell function and mass in the offspring during first month of life as
well as the role of ERs.
We use OF1 mice to investigate the effects of BPA on pancreas development in
the offspring exposed. To uncover the possible participation of ERβ animals from
BERKO colony were included in the study. Pancreatic β-cell mass and
proliferation was analysed in the offspring at postnatal day 0 (P0) and 30 (P30)
by means of histological and morphometric procedures. Pancreatic β-cell function
was explored at P30. Glucose tolerance, insulin sensitivity, in vivo and ex vivo
insulin secretion response, changes on gene expression as well plasma levels of
hormones key in glucose and energy homeostasis were analysed. In addition to
that, in order to explore ERβ role in the proliferative effect of BPA in pancreatic
β-cells, a series of in vitro experiments were performed. Dispersed pancreatic
islet cells from adult male WT and BERKO mice were cultured in the presence of
vehicle or BPA, a specific agonist of ERβ, WAY200070, a specific agonist of ERα,
PPT, or the natural hormone 17β-estradiol.
We found that gestational exposure to BPA led to a significant increase of
pancreatic β-cell area and mass in the OF1 male offspring. This increment was
related to enhanced pancreatic β-cell proliferation rate and decreased apoptosis.
Similar results were observed in WT exposed animals from the BERKO colony
while mice lacking ERβ did not show any change. In vitro experiments revealed
that BPA, at environmentally relevant doses, promoted increased pancreatic β-
cell division in an ERβ-dependent manner. Nevertheless, we cannot discard that
other ERs like ERα may also play a role since the treatment with the selective
agonist of ERα, PPT, also increased β-cell replication rate. On the contrary, the
treatment with 17β-estradiol, in the same range of doses, did not promote any
change on β-cell proliferation neither in males nor in females WT. As regards the
in vivo study of glucose homeostasis, no significant effects were observed on
glucose tolerance, insulin sensitivity or plasma hormone levels in the male
offspring in utero exposed to BPA at P30. However, we do observe that BERKO
animals showed decreased insulin secretion in response to stimulatory glucose
concentrations. In summary, in the present study we demonstrate that in utero exposure to BPA
promote early changes in the morphology of the endocrine pancreas in an ERβ-
dependent manner. In addition, we found that BPA, at doses within the range of
human exposure, modulates pancreatic β-cell division leading to an increment of
pancreatic β-cell mass during development. This finding will contribute to expand
our knowledge on the mechanisms underlying BPA action which may have an
impact on glucose homeostasis.
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