Most significant effects were observed for BPA doses within one o

Most significant effects were observed for BPA doses within one order of magnitude around the current TDI of 50 μg/kg/day. Conversely, virtually no effects were observed at the NOAEL (5,000 μg/kg/day). Agencies for risk assessment have established

a “safe” TDI for BPA at 50 μg/kg/day, but several studies have revealed that exposure to environmentally relevant BPA doses below the TDI alters various biological functions, including reproductive, behavioral, metabolic, and immune systems.4 However, the molecular mechanisms underlying these low-level responses are still unknown. It was proposed that down-regulation of receptors at higher hormone or xenoestrogen levels may contribute to shape these nonmonotonic curves. Some of BPA’s actions, including insulin production by the pancreas, were attributed to its ability to bind to nonclassical membrane estrogen receptor as well as the G-protein coupled-receptor 30 (GPR30) Ibrutinib price and to act through nongenomic pathways.20, 30 Interestingly, we observed that, contrary to lipid metabolism genes, Ugt1a1 expression displayed a dose-dependent increase in response to BPA (Fig. 3E). Human UGT1a1 mRNA expression has been previously reported to be increased by low BPA doses in HepG2 cells.31 This phase II enzyme is involved in the metabolism of endogenous estrogens32 and has also been shown to catalyze BPA

glucuronidation at high substrate concentration.33 Whether the modest increase in Ugt1a1 expression can interfere with Selleck INCB024360 the action of BPA and/or find more endogenous estrogens may be doubtful, but it suggests that different pathways with different sensitivities to BPA are targeted depending on the dose of exposure. The effects of BPA on insulin expression and secretion have been described.17 Our results strongly

suggest that the effects of BPA on insulin production by the pancreas translate to transcriptional and functional consequences in the liver. Indeed, insulin is known to increase glycolysis and lipogenesis by way of both posttranslational protein modifications and transcriptional mechanisms.34 SREBP-1c plays a major role in the regulation of these genes in response to insulin.35 LXR is thought to contribute to the effect of insulin on Srebp-1c gene expression.36 LXR also directly regulates the expression of lipogenic genes.37 Additionally, insulin also stimulates the proteolytic processing of SREBP-1c,38 leading to increased mature nuclear form and subsequent induction of lipogenic gene expression. In addition to insulin, glucose stimulates glycolytic and lipogenic gene expression by activating the ChREBP,29 which is itself under the transcriptional control of LXR.39 Insulin also induces the expression of Spot14, which is required for induction of hepatic lipogenesis by thyroid hormone and insulin40, 41 and of Pnpla3 by way of SREBP1-c.42 SREBP-2 expression and activity are primarily regulated by low sterol levels but were also reported to respond to increased insulin levels.

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