Reduced body weight at weaning followed by increased post-weaning growth rate interacts with part-per-trillion fetal serum concentrations of bisphenol A (BPA) to impair glucose tolerance in male mice.

Julia A. Taylor,Chun-Xia Meng,Frederick S. vom Saal,Susan C. Nagel,Toshi Shioda,Jennifer M. Sommerfeld-Sager,Nick Ashton

doi:10.1371/journal.pone.0208846

Abstract

There is evidence from longitudinal studies that being light at birth and weaning is associated with subsequent rapid weight gain in infants. This is referred to as “centile crossing”, which can lead to increased risk of lifetime obesity, glucose dysregulation and type 2 diabetes. Here, pregnant CD-1 mice were hemi-ovariectomized so that the entire litter was contained in one uterine horn to increase variability in fetal growth rate. Pregnant females were implanted on gestation day (GD) 9 with a Silastic capsule containing 6, 60 or 600 μg bisphenol A (BPA). On GD 18 the mean fetal serum unconjugated BPA concentrations were 17, 177 and 1858 pg/ml, respectively. Capsules were not removed, to avoid maternal stress, and were predicted to release BPA for at least 3 weeks. Body weight at weaning was strongly negatively correlated with post-weaning weight gain in both control and BPA-treated male mice, consistent with human data; female offspring were excluded, avoiding complications associated with postpubertal estrogens. Within each treatment group, male offspring were sorted into tertiles based on relative weight gain during the two weeks after weaning, designated as having Rapid (R), Medium (M) or Slow (S) growth rate. BPA exposure was associated with altered growth rate between weaning and postnatal week 12 (young adulthood), when a low-dose (20 mg/kg, i.p.) glucose tolerance test (GTT) was performed. We found altered glucose regulation in response to all doses of BPA. However, glucose tolerance was only significantly impaired (blood glucose levels were elevated) compared to controls in males in the rapid post-weaning growth group exposed perinatally to BPA. We conclude that male mice that are light at weaning, but then experience rapid catch-up growth immediately after weaning, represent a sensitive sub-population that is vulnerable to the metabolic disrupting effects of very low pg/ml fetal serum concentrations of BPA.

Highlights

Decades ago type 2 diabetes was considered an adult-onset disease
In CD-1 mice exposed to capsules containing 6, 60 or 600 μg bisphenol A (BPA) spiked with 3H-BPA, mean fetal serum concentrations of unconjugated BPA on gestation day (GD) 18 were 16.6, 176.5 and 1857.6 pg/ml, respectively
We measured unconjugated and conjugated BPA in the pups on PND2, the presence of which may have been due to residual BPA from the prenatal, transplacental exposure and/or transfer from mother to pup via nursing, since the capsules were not removed from the mothers at parturition to avoid the stress associated with surgery

Summary

Introduction

Decades ago type 2 diabetes was considered an adult-onset disease. Adolescents and even children have experienced significant increases in both obesity and type 2 diabetes over short periods of time [1, 2]. The consequence of the increase in disease burden associated with diabetes and obesity is that children born in the 21st century are not predicted to have the life expectancy of their parents [4]. The risk for obesity and other components of metabolic disease is highest in two subgroups of infants: those that are born heavy and remain heavy, and those that are light at birth and experience accelerated early childhood growth [5], a phenomenon known as “centile crossing”. Growth velocity during the first few years of life is important as a predictor of adult obesity in people [6], which is a predictor of glucose dysregulation leading to insulin resistance and type 2 diabetes [3]. Determining the factors that contribute to glucose dysregulation and other co-morbidities of metabolic syndrome has become a major public health issue [3]

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Conclusion