Effects of Low Doses of Bisphenol a on the Metabolome of Perinatally Exposed CD-1 Mice
Cabaton, Nicolas J., Canlet, Cecile, Wadia, Perinaaz R., Tremblay-Franco, Marie, Gautier, Roselyne, Molina, Jerome, Sonnenschein, Carlos, Cravedi, Jean-Pierre, Rubin, Beverly S., Soto, Ana M., Zalko, Daniel, Environmental Health Perspectives
Bisphenol A (BPA) is manufactured at a rate of > 3.1 million tons/year; thus, exposure to this compound is ubiquitous. Its possible impact on human health is reflected in recent worldwide regulatory legislation. For example, the Canadian authorities, followed by the European Union, have recently banned the use of BPA in infant feeding bottles, a landmark move to safeguard the health of infants and the general population (Asimakopoulos et al. 2012; European Commission 2011). Nevertheless, BPA is still widely used in polycarbonates, epoxy resins, paints, lacquers, and medical devices. BPA is also used as a base compound for the manufacture of flame retardants, brake fluids, and thermal papers (Fernandez et al. 2007). BPA monomers migrate out of these products and contaminate, for example, food, beverages, and intravenous infusions, (Goodson et al. 2004). Although the main route of contamination is through ingestion, the transdermal route could also contribute to BPA exposure in humans when direct contact with BPA (free monomer) occurs (Zalko et al. 2011). Detectable levels of BPA were present in urine samples of > 92% of Americans tested in the 2003-2004 National Health and Nutrition Examination Survey (Calafat et al. 2008). Higher exposure levels were found in children and adolescents compared with adults. Of particular concern is the finding of high levels of BPA in premature infants being treated in neonatal intensive care units (Calafat et al. 2009). BPA has also been detected in maternal and fetal plasma, in human placenta, and in the milk of nursing mothers (Calafat et al. 2006; Sun et al. 2004). Animal studies have highlighted the estrogenic effects of BPA (vom Saal et al. 2007), although BPA is considered by some to be a weak estrogen due to its low potency compared with estradiol in reporter gene assays involving nuclear receptors (Blair et al. 2000). However, recent work has shown that BPA can be as potent as or more potent than estradiol in promoting some estrogenic activities (Alonso-Magdalena et al. 2006, 2012). BPA can also bind to membrane receptors (G protein-coupled receptor 30 and the membrane form of estrogen receptor-[alpha]) to produce effects similar to those of estradiol (Thomas and Dong 2006; Welshons et al. 2006; Wozniak et al. 2005).
Perinatal BPA exposure has been reported to decrease fertility and fecundity in female CD-1 mice (Cabaton et al. 2011) and to decrease fertility in male offspring of exposed rats (Salian et al. 2011). Additional effects of perinatal BPA exposure include masculinization of behaviors and brain structures in female CD-1 mice (Richter et al. 2007; Rubin et al. 2006). Exposure to BPA through placenta and milk has been shown to increase early adipose storage and adipogenesis in a sex-specific and dose-dependent manner in rats and mice, with consequences on body weight later in life (Rubin and Soto 2009; Somm et al. 2009). BPA exposure has been linked to altered glucose homeostasis in pregnant female rodents and their male offspring (Alonso-Magdalena et al. 2010) and has been postulated to be a contributing factor in predisposing populations to the development of obesity and diabetes later in life (Heindel and vom Saal 2009; vom Saal et al. 2012).
The aim of metabonomics is to measure the "global, dynamic metabolic response of living systems to biological stimuli" (Nicholson and Lindon 2008). Metabolomics have furthered our understanding of drug toxicology while complementing more traditional approaches (Coen 2010). The integration of metabolomics and conventional toxicological studies is expected to provide valuable information for risk assessment of endocrine disruptors (EDs) such as BPA. Metabolic fingerprints based on nuclear magnetic resonance (NMR) spectroscopy, combined with appropriate statistical methods, could detect slight changes in the metabolome of cells, tissues, or organisms exposed to EDs, opening the way to examine whether exposure to an ED results in global alterations of metabolism and whether these changes persist after cessation of exposure. …