Oxidative stress, unfolded protein response, and apoptosis in developmental toxicity

Abstract

Physiological development requires precise spatiotemporal regulation of cellular and molecular processes. Disruption of these key events can generate developmental toxicity in the form of teratogenesis or mortality. The mechanism behind many developmental toxicants remains unknown. While recent work has focused on the unfolded protein response (UPR), oxidative stress, and apoptosis in the pathogenesis of disease, few studies have addressed their relationship in developmental toxicity. Redox regulation, UPR, and apoptosis are essential for physiological development and can be disturbed by a variety of endogenous and exogenous toxicants to generate lethality and diverse malformations. This review examines the current knowledge of the role of oxidative stress, UPR, and apoptosis in physiological development as well as in developmental toxicity, focusing on studies and advances in vertebrates model systems.

Keywords: Apoptosis; Developmental toxicity; ER stress; Oxidative stress; Teratogenesis; Unfolded protein response.

Figure 1. Endogenous formation of reactive oxygen species/reactive nitrogenspecies

Abbreviations: COX, cyclooxygenase; CYP450, cytochrome P 450; NOX, NADPH oxidase; NOS, nitric oxide synthase; SOD, superoxide dismutase; XO, xanthine oxidase.

Figure 2. Damage and protection from reactive oxygen species

Abbreviations: CAT, catalase; GSH, glutathione; GR, glutathione reductase; Grx, glutaredoxin; GSSG, glutathione disulfide; Prx, peroxiredoxin; R–SH, protein thiol group; R–SS–R, protein with disulfide bond; SOD, superoxide dismutase; Trx, thioredoxin; TrxR, thioredoxin reductase.

Figure 3. Redox-regulated transcription factors

Abbreviations: AP-1, activator protein 1; ATF, activating transcription factor; HIF-1α, hypoxia-inducible factor 1α, Keap1, Kelch-like ECH-associated protein 1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear factor (erythroid-derived 2)-like 2; PHD, prolyl hydroxylase; Ref-1, redox effector factor 1.

Figure 4. The three branches of the unfolded protein response

Abbreviations: ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; BiP, immunoglobulin heavy-chain-binding protein; eIF2α, eukaryotic initiation factor 2α, IRE1, inositol-required enzyme 1; PERK, protein kinase RNA-like ER kinase; RIDD, regulated IRE1-dependent decay; SP1/2, serine proteases 1 and 2; XBP-1, X-box protein 1.

Figure 5. Extrinsic and intrinsic apoptosis

Abbreviations: Apaf-1, apoptotic protease activating factor 1; BAK, Bcl-2 homologous antagonist/killer; BAX, BCL2-associated X; Bcl-2, B-cell lymphoma 2; c-FLIP, cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein; Casp, caspase; CytC, cytochrome C; FADD, Fas-associated protein with death domain; FAS-L, FAS ligand; PC, procaspase.

Figure 6

Apoptosis in physiological development.

Figure 7. Interplay between the unfolded protein response and redox potential

Abbreviations: ATF4, activating transcription factor 4; BiP, immunoglobulin heavy-chain-binding protein; CHOP, C/EBP homologous protein; eIF2α, eukaryotic initiation factor 2α; ERO1, ER oxidoreductin 1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear factor (erythroid-derived 2)-like two; PDI, protein disulfide isomerase; PERK, protein kinase RNA-like ER kinase.

Figure 8. Oxidative stress-induced apoptosis

Abbreviations: Apaf-1, apoptotic protease activating factor 1; BAX, BCL2-associated X; CytC, cytochrome C; DR5, death receptor 5; HIPK2, homeodomain interacting protein kinase 2; MPT, mitochondrial permeability transition; PUMA, p53-upregulated modulator of apoptosis; TRAIL, TNF-related apoptosis-inducing ligand; XO, xanthine oxidase.

Figure 9. Oxidative stress induced by the unfolded protein response

Abbreviations: ASK1, apoptosis signal-regulating kinase 1; ATF4, activating transcription factor 4; BAX, BCL2-associated X; Bcl-2, B-cell lymphoma 2; Casp, caspase; CHOP, C/EBP homologous protein; eIF2α, eukaryotic initiation factor 2α, ERO1, ER oxidoreductin 1; IRE1, inositol-required enzyme 1; JNK, c-Jun N-terminal kinase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PERK, protein kinase RNA-like ER kinase; RIDD, regulated IRE1-dependent decay; TRAF2, TNF receptor-associated factor 2; XBP-1, X-box protein 1.

Figure 10. The unfolded protein response and oxidative stress induction by hypoxia

Abbreviations: CI and CIII, complex I and III; ERO1, ER oxidoreductin 1; HIF, hypoxia-inducible factor; NOX, NADPH oxidase; XO, xanthine oxidase; XBP-1, X-box protein 1.

Figure 11. Hyperglycemic induction of oxidative stress

Abbreviations: GSH, glutathione; iNOS, inducible nitric oxide synthase; JNK, c-Jun N-terminal kinases; NOX, NADPH oxidase; PKC, protein kinase C.

Figure 12. Potential mechanisms of alcohol-induced ER stress and oxidativestress

Abbreviations: NOS, nitric oxide synthase; NOX, NADPH oxidase.

Figure 13

Interplay between the unfolded protein response, oxidative stress, and apoptosis in developmental toxicity.