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. 2014 Jun 24;9(6):e100214.
doi: 10.1371/journal.pone.0100214. eCollection 2014.

Exposure to bisphenol-A during pregnancy partially mimics the effects of a high-fat diet altering glucose homeostasis and gene expression in adult male mice

Marta García-Arevalo  1 , Paloma Alonso-Magdalena  2 , Junia Rebelo Dos Santos  3 , Ivan Quesada  4 , Everardo M Carneiro  5 , Angel Nadal  1
Affiliations

Exposure to bisphenol-A during pregnancy partially mimics the effects of a high-fat diet altering glucose homeostasis and gene expression in adult male mice

Marta García-Arevalo et al. PLoS One. .

Abstract

Bisphenol-A (BPA) is one of the most widespread EDCs used as a base compound in the manufacture of polycarbonate plastics. The aim of our research has been to study how the exposure to BPA during pregnancy affects weight, glucose homeostasis, pancreatic β-cell function and gene expression in the major peripheral organs that control energy flux: white adipose tissue (WAT), the liver and skeletal muscle, in male offspring 17 and 28 weeks old. Pregnant mice were treated with a subcutaneous injection of 10 µg/kg/day of BPA or a vehicle from day 9 to 16 of pregnancy. One month old offspring were divided into four different groups: vehicle treated mice that ate a normal chow diet (Control group); BPA treated mice that also ate a normal chow diet (BPA); vehicle treated animals that had a high fat diet (HFD) and BPA treated animals that were fed HFD (HFD-BPA). The BPA group started to gain weight at 18 weeks old and caught up to the HFD group before week 28. The BPA group as well as the HFD and HFD-BPA ones presented fasting hyperglycemia, glucose intolerance and high levels of non-esterified fatty acids (NEFA) in plasma compared with the Control one. Glucose stimulated insulin release was disrupted, particularly in the HFD-BPA group. In WAT, the mRNA expression of the genes involved in fatty acid metabolism, Srebpc1, Pparα and Cpt1β was decreased by BPA to the same extent as with the HFD treatment. BPA treatment upregulated Pparγ and Prkaa1 genes in the liver; yet it diminished the expression of Cd36. Hepatic triglyceride levels were increased in all groups compared to control. In conclusion, male offspring from BPA-treated mothers presented symptoms of diabesity. This term refers to a form of diabetes which typically develops in later life and is associated with obesity.

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Conflict of interest statement

Competing Interests: Please note that co-author Angel Nadal is a member of the PLOS ONE editorial board. This does not alter the authors' adherence to PLOS ONE Editorial Policies and Criteria.

Figures

Figure 1
Figure 1. Body weight and calorie intake in the four study groups.
A) Body weight evolution from 4 weeks to 28 weeks old. Animals were started on the HFD at 4 weeks. Arrows indicate weeks 17 and 28, the age when experiments were done (n = 150 animals from 26 litters). B) Body weight of offspring from the four different groups at 17 weeks (Control n = 46 animals from 8 litters, BPA n = 28 from 5 litters, HFD n = 38 from 8 litters and HFD-BPA n = 30 from 5 litters). C) Body weight of offspring from the four different groups at 28 weeks (Control n = 19 animals from 8 litters, BPA n = 15 from 5 litters, HFD n = 26 from 8 litters and HFD-BPA n = 15 from 5 litters), *P<0.01 Student's t-test compared to Control. D) Food intake for the four different groups compared at 17 weeks old (n = 142 animals from 26 litters) E) Food intake for the four different groups compared at 28 weeks old (n = 75 animals from 26 litters). Data are expressed as mean±SEM. Significance by one way ANOVA followed by Tukey, Holm-sidak or Dann's method, p<0.05. b compares control vs. HFD, c control vs. HFD-BPA, d HFD vs. BPA, e HFD vs. HFD-BPA, f BPA vs. HFD-BPA.
Figure 2
Figure 2. Adipose tissue weight and plasma NEFA levels in offspring.
A) Perigonadal and B) Retroperitoneal fat depots, expressed as % of body weight at 17 weeks old (n = 8 animals from 5–8 litters). C) Perigonadal and D) Retroperitoneal fat depots, expressed as % of body weight at 28 weeks old. (n = 6–8 animals from 5–8 litters). E) Plasma Nonesterified fatty acids (NEFAs) levels at 17 weeks old (n = 7–9 animals from 7 litters) and F) 28 weeks old (n≥5 animals from 4–7 litters). Data are expressed in mean ±SEM; significance p<0.05 by one way ANOVA followed by Holm-Sidak or Dunnett's method; a control vs. BPA; b control vs. HFD, c control vs. HFD-BPA, d HFD vs. BPA, e HFD vs. HFD-BPA, f BPA vs. HFD-BPA.
Figure 3
Figure 3. BPA, HFD and HFD-BPA groups exhibit hyperglycaemia and glucose intolerance.
A) ipGTT were performed on the four groups at 17 weeks old. The inset shows mean±SEM of the ipGTT Area Under the Curve (n≥6 animals from ≥6 litters). B) ipITT in 17 week old animals (n≥6 animals from ≥6 litters) C) ipGTT were performed on the four groups at 28 weeks old. The inset shows mean±SEM of the ipGTT Area Under the Curve (n≥12 animals from ≥6 litters). D) ipITT in 28 week old animal. (n≥11 animals from ≥6 litters). Data are expressed in mean±SEM. Significance P<0.05 by one way ANOVA followed by Tukey or Dunnett's method; a control vs. BPA; b control vs. HFD, c control vs. HFD-BPA, d HFD vs. BPA, e HFD vs. HFD-BPA, f BPA vs. HFD-BPA.
Figure 4
Figure 4. Glucose-induced insulin secretion from isolated islets.
A) Insulin secretion from islets exposed to 3, 8 and 16 mM glucose for 1 hour, in animals from the four different groups at the age of 17 weeks. (n≥9 experiments with 7 animals from 7 litters). The inset shows the insulin release when islets were exposed to 3 mM of glucose. B) Insulin secretion from islets exposed to 3, 8 and 16 mM of glucose for 1 hour, in animals from the four different groups at the age of 28 weeks (n≥6 experiments with ≥6 animals from ≥6 litters). C) Insulin content from isolated islets at the age of 17 weeks (n≥10 experiments with 7 animals from 7 litters). D) Insulin content from isolated islets at 28 weeks (n≥8 experiments with ≥6 animals from ≥6 litters). Data are expressed in mean±SEM, p<0.05 by one way ANOVA followed by Tukey, Dunnet or Dunn's method; a control vs. BPA; b control vs. HFD, c control vs. HFD-BPA, d HFD vs. BPA, e HFD vs. HFD-BPA, f BPA vs. HFD-BPA.
Figure 5
Figure 5. mRNA gene expression associated with A) Lipogenesis, B) Fatty Acid Uptake, C) Fatty Acid Oxidation and D) Glucose Uptake and Metabolism, in White Adipose Tissue (WAT) from Control (n≥5 animals from ≥5 litters), BPA (n≥5 animals from ≥5 litters), HFD (n≥5animals from ≥5 litters) and HFD-BPA (n≥5 animals from ≥5 litters) dams at 17 weeks old.
Animals were treated with HFD at week 4. Gene expression was assessed by real-time RT-PCR. Data are expressed as mean±SEM and statistical significance was determined using one way ANOVA followed by Tukey, Duncans or Dunn's method. Significance p<0.05; a compared control vs. BPA; b control vs. HFD, c control vs. HFD-BPA, d HFD vs. BPA, e HFD vs. HFD-BPA, f BPA vs. HFD-BPA.
Figure 6
Figure 6. mRNA gene expression associated with A) Lipogenesis, B) Fatty Acid and Glucose Uptake, C) Fatty Acid Oxidation and D) Glucose Metabolism, in the liver from Control (n≥5animals from ≥5 litters), BPA (n≥5 animals from ≥5 litters), HFD (n≥5 animals from ≥5 litters) and HFD-BPA (n≥5 animals from ≥5 litters) dams at the age of 17 weeks.
Animals started to be treated with HFD at the age of 4 weeks. Gene expression was assessed by real-time RT-PCR. E) Hepatic trygliceride content from Control (n≥5animals from ≥5 litters), BPA (n≥5 animals from ≥5 litters), HFD (n≥5 animals from ≥5 litters) and HFD-BPA (n≥5 animals from ≥5 litters) dams at the age of 17 weeks. Data are expressed as mean±SEM and statistical significance was determined using one way ANOVA followed by Tukey or Dunn's method. Significance p<0.05; a compares control vs. BPA; b control vs. HFD, c control vs. HFD-BPA, d HFD vs. BPA, e HFD vs. HFD-BPA, f BPA vs. HFD-BPA.
Figure 7
Figure 7. mRNA gene expression associated with A) Fatty Acid Oxidation and B) Fatty Acid and Glucose Uptake and Metabolism, in Skeletal Muscle from Control (n≥5 animals from ≥5 litters), BPA (n≥5 animals from ≥5 litters), HFD (n≥5 animals from ≥5 litters) and HFD-BPA (n≥5 animals from ≥5 litters) dams at the age of 17 weeks.
Animals started to be treated with HFD at week 4. Gene expression was assessed by real-time RT-PCR. Data are expressed as mean±SEM and statistical significance was determined using one way ANOVA followed by Duncan or Dunn's method. Significance p<0.05; a compared control vs. BPA; b control vs. HFD, c control vs. HFD-BPA, d HFD vs. BPA, e HFD vs. HFD-BPA, f BPA vs. HFD-BPA.
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Grants and funding

This research was supported by grants from Ministerio de Economia y Competitividad grants, BFU2011-28358 and BFU2010-21773, and Generalitat Valenciana grants Prometeo/2011/080 and ACOMP/2010/113. The “Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas” is an initiative of the Instituto de Salud Carlos III. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.