Proposed schematic of the effect of nicotine on ER stress and the unfolded protein response in the e15 placenta.

<p>Pathways affected by nicotine are indicated by the darkened arrows and boxes. In summary, nicotine exposure was shown to augment ER stress and activate the unfolded protein response in the e15 placenta. Activation was most prominent in the PERK branch and was demonstrated in association with impaired disulfide bond formation. Nicotine is proposed to impair disulfide bond formation through direct or indirect down-regulation of PDI and other oxidoreductases. Disulfide bond formation is further impaired through increased hypoxia as caused by nicotine-induced vasoconstriction. Additionally, up-regulation of GCN2 suggests amino acid starvation and activation of the integrated stress response to further phosphorylate eIF2α. However, the lack of Bax and caspase activation seen at e15 suggests that the nicotine-induced ER stress response may possibly be attempting to avoid apoptosis by re-establishing some manner of sub-optimal placental homeostasis to adapt to the ER stress experienced.