Bisphenol-A (BPA), is anenvironmental chemical that exerts hormone-like activity and interferes with the function of endogenous hormones, such as estrogen. Hence termed an estrogenic endocrine distrupting chemical (EDCs), BPA isis one of the highest volume chemicals in worldwide production, with production capacity estimated at 10-billion pounds per year in 2011, for use in manufacturing polycarbonate plastic, the resin that lines metal cans, and as an additive in many other types of plastic. All human fetuses that have been examined have measurable blood levels of BPA.

Effects of estrogen on weight in adults.

The typical view of estrogen is that it is associated with a reduction in food intake and body weight in adults, and theloss of ovarian estrogen secretion associated with menopause inwomen results in weight gain.

However, evidence is accumulating that during critical periods in development,estrogenic chemicals can have unexpected effects on the differentiation of adipocytes as well as postnatal growth. Estrogen caninhibit adipose deposition by decreasing lipogenesis. Estrogen has this effect as itdecreases the activity of lipoprotein lipase (LPL), an enzyme that regulates lipid uptake by adipocytes. As such, a low LPL level can result in a lower level of lipid uptake.

Adult mice estradiol has been found to act via (estrogen receptor alfa) ER to have aninhibitory effect on adipocyte number and lipogenesis, andremoval of estrogen by ovariectomy or via a genetic mutation also causes impaired glucose tolerance and insulin resistance in addition to increased fat mass.

Estrogen has central effects on food consumption and energy expenditure that also contribute to its overall inhibitory effects on adipose deposition in adults.17-estradiol (E2) is normally considered the most potent and important estrogen. Besides this sexual and reproductive role, we know that E2 exerts a large number of actions in other systems such as the bone, liver, brain, endocrine pancreas, adipose tissue, skeletal muscle and cardiovascular systems (Gustafsson, 2003 and Heldring et al., 2007).

BPA's mechanism of action as an EDC

BPA has been found to bind to estrogen receptors and have estrogenic effects in laboratory studies.

Although BPA has been found to have alower affinity for nuclear estrogen receptors relative to E2, its estrogenicpotency is equal to E2 for responses mediated by non-nuclear estrogen receptors. Further,BPA can act as an antiestrogen, blocking the estrogenic response by competing with endogenous E2.

Previously, BPA was considered a weak estrogen since its binding affinity to the estrogen receptors alfa (ER) and beta (ER) was estimated to be over 100010,000-fold lower than the natural hormone E2 ( half maximal effective concentration: EC50 = 27 107 M compared to 16 1013 M for E2) (Kuiper et al., 1998, Andersen et al., 1999 and Fang et al., 2000). BPA selectively binds to ER and ER although it has a higher affinity for ER (Kuiper et al., 1997, Matthews et al., 2001 and Routledge et al., 2000). In some cell types, it has been proposed that BPA exhibits estradiol-like agonist activity via ER and a mixed agonist and antagonist activity via ER (Kurosawa et al., 2002).

Recent studies have revealed that BPA can promote estrogen-like activities that are similar or stronger than E2(Alonso-Magdalena et al., 2005, Alonso-Magdalena et al., 2006, Hugo et al., 2008 and Zsarnovszky et al., 2005).BPA at nanomolar doses often displays stronger estrogen-like activities than E2 itself.These low dose effects can be explained at least partially becauseBPA elicits rapid responses via non-classical estrogen triggered pathways(Nadal et al., 2000, Quesada et al., 2002 and Watson et al., 2005).

BPA's effect on the differentiation of adipocytesBPA triggers adipocyte differentiation: The confluent cultures of 3T3-L1 fibroblasts treated with BPA presented an increase in tri-glyceride content, lipoprotein lipase activity, and glycerol phosphate dehydrogenase activity, suggesting thatBPA by itself can promote 3T3-L1 fibroblasts to differentiate into adipocytes(Masuno et al. 2002).3T3-L1 cells treated with BPA also show increased levels of lipoprotein lipase and adipocyte-specific fatty acid binding protein (aP2) mRNAs, confirming thatBPA is able to accelerate the terminal differentiation of 3T3-L1 cells into adipocytes(Masuno et al. 2005)BPA induces adipocyte differentiation through a non-classical ER-mediated mechanismrather than through GR activation. These results indicate thatBPA can contribute to the final maturation of cells committed to the adipocyte lineageand add to the growing body of evidence that BPA acts as an obesogen.(J G Boucher, A Boudreau and E Atlas, 2014)

BPA's effect on adipocyte function

Adipose stem cells (ASCs), treated with BPA demonstrated a 1.67 (+/-)0.13-fold increase in adipogenic differentiation following treatment with BPA.ASCs treated with 100 nM and 1 mM BPA demonstrated a significant increase in adipogenesis, with a maximal response observed at a concentration of 1 mM BPA (1.67G0.13-fold increase) with cytotoxicity observed in treatments at a concentration of 10 mM. This suggest that thehigher the concentration of BPA, the greater the increase in adipogenesis.BPA enters into ASCs and increases the transcription of several key adipogenic genes through an ER-dependent pathway.(J F Ohlstein, 2014)

However, asignificant increase in adipogenesis in ASCs treated for 14 days at levels as low as 100 pM was observed.(J F Ohlstein, 2014)This puts forth the hypothesis that low doses of BPA present environmentally may be sufficient to increase adipogenesis.

BPA's effect on adiponectin

Adiponectin is an adipocyte-specific hormone that protects against metabolic syndrome (Kadowaki, 2006). Adiponectin increases insulin sensitivity and decreases tissue inflammation. (Whitehead, 2006 ) As such,lowered levels of adiponectin are correlated with an increase in insulin resistance.Serum adiponectin levels are reduced before development of type 2 diabetes and are lower in obese individuals.(E R Hugo, 2008)

BPA significantlyinhibited adiponectin release from mature adipocytesat most doses examined, albeit without exhibiting dosedependent effects. (E R Hugo, 2008)The inhibition of adiponectionincreases the risk of metabolic syndrome, which isdefined by a cluster of conditions that include abdominal obesity, glucose intolerance, hyperinsulinemia, hypertriglyceremia, and hypertension and is associated with increased risk of diabetes and cardiovascular disease (Ritchie and Connell 2007)