Abstract
Along with the well-established effects on fertility and fecundity, perinatal exposure to endocrine disrupting chemicals, and notably to xeno-estrogens, is strongly suspected of modulating general metabolism. The metabolism of a perinatally exposed individual may be durably altered leading to a higher susceptibility of developing metabolic disorders such as obesity and diabetes; however, experimental designs involving the long term study of these dynamic changes in the metabolome raise novel challenges. 1H-NMR-based metabolomics was applied to study the effects of bisphenol-A (BPA, 0; 0.25; 2.5, 25 and 250 μg/kg BW/day) in rats exposed perinatally. Serum and liver samples of exposed animals were analyzed on days 21, 50, 90, 140 and 200 in order to explore whether maternal exposure to BPA alters metabolism. Partial Least Squares-Discriminant Analysis (PLS-DA) was independently applied to each time point, demonstrating a significant pair-wise discrimination for liver as well as serum samples at all time-points, and highlighting unequivocal metabolic shifts in rats perinatally exposed to BPA, including those exposed to lower doses. In BPA exposed animals, metabolism of glucose, lactate and fatty acids was modified over time. To further explore dynamic variation, ANOVA-Simultaneous Component Analysis (A-SCA) was used to separate data into blocks corresponding to the different sources of variation (Time, Dose and Time*Dose interaction). A-SCA enabled the demonstration of a dynamic, time/age dependent shift of serum metabolome throughout the rats’ lifetimes. Variables responsible for the discrimination between groups clearly indicate that BPA modulates energy metabolism, and suggest alterations of neurotransmitter signaling, the latter finding being compatible with the neurodevelopmental effect of this xenoestrogen. In conclusion, long lasting metabolic effects of BPA could be characterized over 200 days, despite physiological (and thus metabolic) changes connected with sexual maturation and aging.
Highlights
A variety of anthropogenic compounds act as endocrine disrupting chemicals (EDCs)
We extended our previous study in mice [13] to a study using multiple doses (5) and time points (5) in rats up to PND200, to address the lasting metabolic consequences of perinatal exposure to low doses of BPA, and examined those effects despite physiological changes related to puberty and aging
With the aim of identifying the metabolic fingerprints characteristic of perinatal low dose BPA exposure, high-resolution 1H-Nuclear Magnetic Resonance (NMR) spectra were recorded from serum samples and aqueous liver extracts (Fig 1)
Summary
A variety of anthropogenic compounds act as endocrine disrupting chemicals (EDCs). Adverse effects of EDCs have been documented in humans, in wildlife and in laboratory experiments [1]. The effects observed in animal models parallel the increase of similar pathologies such as obesity, neurobehavioral deficits and breast cancer observed in humans. This is true for xeno-estrogens (and anti-androgens), when exposure occurs during development. Low doses of EDCs produced adverse effects when exposure occurred during specific windows of sensitivity, during early fetal development [2, 3]. In addition to reproductive alterations in rodents of both genders, perinatal exposure studies using DES and bisphenol-A (BPA) as model xeno-estrogens, have unveiled a broader range of deleterious effects on behavior, thyroid and cardiovascular endocrinology [1, 4], even at low doses of exposure [5]. Xeno-estrogens modulate the metabolism, and could contribute to the onset of obesity [6, 7]
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