Table 2.

Pathways Effected in Each Condition Based on Transcripts and Proteins.

Condition	Top 5 Transcript Based Canonical Pathways	Top Upstream Regulators Transcript Based	Other interesting Dysregulated Transcripts and Pathways	Top 5 Protein Based Canonical Pathway	Top Upstream Regulators Protein Based	Other Interesting Dysregulated Proteins and Pathways
1 mo 18O	Mitochondrial dysfunction Oxidative phosphorylation Sirtuin Signaling pathway FXR/RXR activation Fatty Acid beta oxidation I	PPARA Pirin ixic acid POR TO-901317 Mono-(2-ethylhexyl) phthalate	TCA Cycle II, Gluconeogenesis I (aldolase, fructose-bisphosphate C; enolase 1; malate dehydrogenase 1 & 2, phosphoglycerate kinase 1 all down), ubiquinol-10 biosynthesis, mitochondrial L-carnitine shuttle pathway (acyl-coA synthetase long chain family member 1, carnitine palmitoyltransfease 1A & solute carrier family 27 member 5 all down), ceramide signaling	Sirtuin Signaling Pathway RhoA Signaling (cytoskeleton organization) Clathrin-mediated Endocytosis signaling LXR/RXR activation Actin Cytoskeleton Signaling	HNF4A-hepatocyte nuclear factor 4 alpha Insulin D-glucose Methylprednisolone ABCB6	PI3K (down) mTOR (up) cyclin dependent kinase 2(up) cyclin dependent kinase inhibitor 1B (down) glycogen synthase kinase 3 beta (down) insulin signaling receptor (down) mannose-6-phosphate receptor (down)
2 mo 18O	EIF2 signaling Oxidative phosphorylation Regulation of eIF4 and p70S6K signaling Mitochondrial dysfunction Sirtuin signaling pathway	MLXIPL RICTOR YAP1 MYC MYCN	mTOR signaling, Protein Ubiquitination Pathway, NRF2-mediated oxidative stress response, Unfolded protein response, TCA cycle II (fumarate hydratase, succinate dehydrogenase complex (iron sulfur subunit B, C & D all down)	Huntington’s Disease Signaling (HIP1 down) (HSP40 up) Iron homeostasis signaling pathway ILK signaling Tight Junction Signaling Glycogen Degradation III	HNF4A CST5 Maslinic acid miR-30c-5p (and other miRNAs w/seed GUAAACA) desmopressin	Also see sirtuin signaling and ceramide signaling (SMPD (sphingomyelin phosphodiesterase 4) up)
4 mo 18O	EIF2 signaling Unfolded protein response Regulation of eIF4 and p70S6K signaling Protein Ubiquitination Pathway ER stress pathway-CALR (calreticulin) down, DDIT3 (DNA damage inducible transcript 3) down, EIF2AK3 down, HSP90B1 down, HSPA5 down	XBP1 ERN1 Tunicamycin RICTOR ATF6	mTOR signaling, sirtuin signaling pathway	Acute phase response signaling Clathrin-mediated endocytosis signaling Phagosome maturation Role of JAK family kinases in IL-6 type cytokine signaling FXR/RXR activation	HNF4A CST5 TP53 Methylprednisolone D-glucose	Also see B cell receptor signaling, production of nitric oxide & ROS macrophages, cellular senescence (predicted inhibition), CDKN1B cyclin dependent kinase inhibitor (down), CDK2 cyclin dependent kinase 2-activation of s-phase progression, sumoylation pathway-SAE1(SUMO1 activating enzyme subunit 1), LXR/RXR activation, insulin receptor signaling
9 mo 18O	EIF2 signaling Mitochondrial dysfunction Oxidative phosphorylation Regulation of eIF4 and p70S6K signaling Sirtuin signaling pathway	MLXIPL RICTOR MYC YAP1 CTNNB1	mTOR signaling	Clathrin-mediated endocytosis signaling RhoA signaling Acute phase response signaling Huntington’s disease signaling Signaling by Rho family GTPases	NHF4A RHOJ XBP1 Bvr Sirolimus	Coenzyme A biosynthesis, Sirtuin signaling, heme oxygenase 1 & 2 (down)
12 mo 18O	Mouse Embryonic Stem Cell Pluripotency-ID1 (inhibitor of DNA binding), ID2 down Trans, trans-farnesyl diphosphate biosynthesis-FDPS (farnesyl disphosphate synthase) up Pregnenolone biosynthesis-CYP26A1 up Histidine Degradation VI-same Superpathway of Geranylgeranyldiphosphate biosynthesis I (via Mevalonate)-FDPS up	ACVR2A LTBP4 SMAD1/5 Notch BMP10	Ubiquinol-10 biosynthesis- CYP26A1 up, Role of lipids/lipid rafts in the pathogenesis of influenza-FDPS up	Acute phase response signaling Tight junction signaling IL-8 signaling LXR/RXR activation L-glutamine Biosynthesis II(tRNA-dependent)	HNF4A CST5 Tetrachlorodibenzodioxin GPD1 SLC25A13	L-carnitine shuttle pathway (acyl-CoA synthetase long chain family member 3 (down)) & member 4 (up), phospholipase c signaling, type II diabetes signaling, role of NFAT in regulation of the immune response, CDK2 (down), Unfolded protein response
1 mo 56Fe	PXR/RXR activation LPS/IL-1 mediated inhibition of RXR Function Sirtuin Signaling Pathway Nicotine Degradation II Circadian Rhythm Signaling-ARNTL (aryl hydrocarbon receptor nuclear translocator) up, BHLHE40 (basic helix-loop-helix family member e40) down; CLOCK (clock circadian regulator) up; CRY1 (cryptochrome circadian regulator 1) up; PER1 (period circadian regulator 1) down; PER2 down; PER3 down	RORC RORA PPARA Methylprednisolone NR1I2	Ubiquinol-10 biosynthesis, acyl-CoA hydrolysis	Acute phase response signaling Glycogen degradation III Phagosome maturation Huntington’s Disease signaling Clathrin-mediated endocytosis signaling	TO-901317 Ciprofibrate Nitrofurantoin SCAP ACOX1	Calcium transport I (ATPase sarcoplasmic/ER Ca2+ transporting 2 (down) & ATPase plasma membrane Ca2+ transporting 1 (up)), LXR/RXR (apolipoprotein A5-activates cholesterol efflux), Death receptor signaling (CASP7 inhibits DNA repair (down))
2 mo 56Fe	EIF2 Signaling Acute phase response signaling-exported Regulation of eIF4 and p70S6K signaling-exported list mTOR signaling-exported Production of nitric oxide and ROS in macrophages	Lipopolysaccharide MLXIPL IL1B YAP1 IFNG	Sirtuin signaling pathway, FXR/RXR, NRF2-mediated oxidative stress response	Acute phase response signaling Xenobiotic metabolism signaling NAD salvage pathway II UVB-induced MAPK signaling NF-kB activation by viruses	HNF4A Pregnenolone carbonitrile Pirinixic acid Estrone RAB1B	ceramide signaling (sphingosine kinase 2 (up))
4 mo 56Fe	Unfolded protein response Aldosterone signaling in Epithelial cells Endoplasmic reticulum stress pathway Protein ubiquitination pathway NRF2-mediated oxidative stress response	XBP1 Tunicamycin ERN1 ATF6 1,2-dithiol-3-thione	EIF2 signaling, Regulation of eIF4 and p70S6K signaling mTOR, Glucocorticoid receptor signaling, Sirtuin signaling pathway, insulin receptor signaling	Cell cycle regulation by BTG family proteins Inhibition of ARE-mediated mRNA degradation pathway 5-aminoimidazole ribonucleotide biosynthesis I Dopamine receptor signaling Breast cancer regulation by Stathmin1	HNF4A Camptothecin (+-)-2-hydroxyoleic acid FAS HNRNPH1	Cyclins and cell cycle regulation, regulation of eIF4 & p70S6K signaling, ceramide signaling (different protein that O) sphingosine kinase 2, role of CHK proteins in cell cycle checkpoint, mitochondrial L-carnitine shuttle pathway (acyl-CoA synthetase long chain family member 4 down & solute carrier family 27 member 4 (down), thrombin signaling, mTOR signaling
9 mo 56Fe	Unfolded protein response-CEBPE down, all up ERN1, HSPA8, Hspa1b, HSPH1, MAP3K5 NRF2-mediated oxidative stress response-ACTG1, BACH1, DNAJA1, DNAJB1, FKBP5, GSTP1, MAP3K5 all up Aldosterone signaling in epithelial cells-DNAJA1, DNAJB1, HSP90AA1, HSPA8, HSPA4L, HSPH1 all up Protein Ubiquitination pathway same as above Agranulocyte-adhesion and diapedesis-ACTG1 up, CLDN3 down, CXCL2 (C-X-C chemokine ligand) up, CXCL13 up, IL1R1 (interleukin 1 receptor type 1) up	NR5A2 Lipopolysaccharide Cisplatin Thapsigargin NR1I3	GADD45 signaling-CDKN1A (cyclin dependent kinase inhibitor 1A) up, GADD45G (growth arrest and DNA damage inducible gamma) up LXR/RXR signaling-C4A/C4B (complement C4B), CYP7A1, HMGCR (3-hydroxy-3-methylgutaryl-CoA reductase), IL1R1 (interleukin 1 receptor type 1) all up Asparagine biosynthesis I-ASNS(asparagine synthetase glutamine-hydrolyzing) up, FXR/RXR-C4A/C4B, CYP7A1, FOXA3, SLC10A2 all up, PXR/RXR ER stress pathway-ALAS1, CYP7A1, IGFBP1 all up, PI3K/AKT signaling-CDKN1A up, GDF15 (growth differentiation factor 15) down, HSP90AA1 up, MAP3K5 up, Sirtuin signaling pathway-BCL2L11, GADD45G, MT-ND2, MT-ND4, MT-ND6, PFKFB3 (6-phosphofructo-2 kinase/fructose 2,6-biphosphatase 3) all up Apoptosis signaling-BCL2L11 up, ENDOG down, MAP3K5 up	Purine nucleotides de novo biosynthesis II 5-aminoimidazole ribonucleotide biosynthesis I Regulation of cellular mechanics by calpain protease Acute phase responses signaling Sertoli cell-Sertoli cell junction signaling	TO-901317 Ciprofibrate Diethyl nitrosamine HNF4A ACOX1
12 mo 56Fe	only 6 genes dysregulated all up		Gm23442 Gm25394 Gm25835 Gm26397 Snora78 Snord13 (small nucleolar RNA)	Acute phase response signaling Mechanisms of viral exit from host cells Wnt/beta catenin signaling Endothelin-1 signaling Endometrial cancer signaling	HNF4A Let-7a-5p (and other miRNAs w/seed GAGGUAG) 1,2-dithiol-3-thione Methylprednisolone miR-30c-5p (other miRNAs w/seed GUAAACA)	Sirtuin signaling pathway
1 mo 28Si	Mitochondrial Dysfunction Asparagine Biosynthesis I-ASNS (asparagine synthetase (glutamine-hydrolyzing) down Sirtuin Signaling Pathway-MT-CYB; MT-ND2; MT-ND6Alpha tocopherol degradation-CYP4A11 Oxidative phosphorylation	Actinonin MRPL12 DAP3 MT-TM SIRT3	Ubiquinol-10 biosynthesis	Huntington’s Disease signaling Stearate Biosynthesis I (animals) FAT10 signaling pathway D-myo-inositol (1,4,5,6)-tetraphosphate biosynthesis D-myo-inositol (3,4,5,6)-tetrabiphosphate biosynthesis	HNF4A Glucagon Desmopressin CALCA BCAN	Acyl-CoA hydrolysis
2 mo 28Si	FXR/RXR activation-FOXA2 up, HPX down, RARA down, SAA1 * down Role of Oct4 in Mammalian Embryonic stem cell pluripotency-FOXA2 up, RARA down Acute phase response signaling-HP, HPX (hemopexin), SAA1 * all down TR/RXR activation-HP (haptoglobin) and THRSP (thyroid hormone responsive)	Lipopolysaccharide TNF RORC IL1B NR1H4		Acute phase response signaling Fcy receptor mediated phagocytosis in macrophages and monocytes Stearate biosynthesis I (animals) Caveolae-mediated endocytosis signaling Leukocyte extravasation signaling	HNF4A miR-1-3p(and other miRNAs w/seed GGAAUGU) ACOX1 ESR1 Fulvestrant
4 mo 28Si	Unfolded protein response-DNAJB9, HSPA5, Hspa1b, SYVN1 (synoviolin 1) all down IL-7 signaling pathway-IGHG1, Ighg2b, Ighg2c all up Phagosome formation-IGHG1, Ighg2b, MARCO (macrophage receptor with collagenous structure) all up Autoimmune thyroid disease signaling-IGHG1, Ighg2b both up Hematopoiesis from pluripotent stem cells-same as above	CLOCK ATF6 Thapsigargin HTT tunicamycin	Phosphatidylethanolamine biosynthesis II (choline kinase alpha up), ER stress pathway (heat shock protein A(HSP70) member 5 down)	Huntington’s Disease Signaling 3-phoshoinsositide degradation D-myo-inositol-5-phosphate metabolism Superpathway of inositol phosphate compounds 3-phosphoinositide biosynthesis	HNF4A miR-30c-5p(and other miRNAs w/seed GUAAACA) PPARA KLF3 SREBF1
9 mo 28Si	Acetone Degradation I (to Methylglyoxal)-CYP2A6 down, CYP2C8 down, CYP4A22 up Stearate biosynthesis I (animals)-ACOT1 down, CYP4A22 up, ELOVL6(ELOVL fatty acid elongase 6) down Nicotine Degradation III-CYP2A6, CYP2C8, UGT1A4 all down Melatonin Degradation I-same as above Nicotine Degradation II-same	STAT5B Pirinixic acid RORC L-triiodothyronine PPARA	Acyl-CoA hydrolysis, ubiquinol-10 biosynthesis	Remodeling of epithelial adherens junctions Caveolar-mediated endocytosis signaling Clathrin-mediated endocytosis signaling Paxillin signaling Integrin signaling	HNF4A ERBB3 IL4 RHOJ ciprofibrate
12 mo 28Si	only 1 gene upregulated		Gm22154	Aldosterone signaling in epithelial cells Protein ubiquitination pathway Stearate Biosynthesis I (animals) Acute phase response signaling FAT10 signaling pathway	Pirinixic acid ELL2 HNF4A CYP2E1 ciprofibrate	sirtuin signaling pathway
1 mo 1 Gy	Stearate Biosynthesis I (animals)-ACOT1 (acyl-CoA thioesterase 1) down; ACOT4 down; CYP4A11 down; FASN (fatty acid synthase) up Superpathway of cholesterol biosynthesis-FDPS (farnesyl diphosphate synthase) up; MVD (mevalonate diphosphate decarboxylase) up; SQLE (squalene epoxidase) up Acyl-CoA hydrolysis-ACOT1; ACOT4 Superpathway of geranylgeranyl diphosphate biosynthesis I (via Mevalonate) TR/RXR activation-BCL3 (B cell CLL/lymphoma 3) up; FASN up; HP (haptoglobin) up	FGR19 PPARA SCAP CFTR SREBF1	Palmitate biosynthesis I, ubiquinol-10 biosynthesis	Sirtuin signaling pathway Antigen presentation pathway Phagosome maturation Remodeling of epithelia adherens junctions Molybdenum cofactor biosynthesis	HNF4A POR SREBF1 SCAP ESR1	PTEN signaling, sumoylation, death receptor signaling
2 mo 1 Gy	EIF2 signaling mTOR signaling Regulation of eIF4 and p70S6K signaling Unfolded protein response Complement system	MLXIPL Lipopolysaccharide YAP1 IL6 CTNNB1	Ubiquinol-10 biosynthesis, sphingosine-1-phosphate signaling	Stearate Biosynthesis I (animals) 3-phosphoinositide degradation Clathrin-mediated endocytosis signaling 3-phosphoinositide biosynthesis D-myo-inositol (1,4,5,6)-tetra bisphosphate biosynthesis	CFTR TO-901317 Pirinixic acid HNF4A PPARA
4 mo 1 Gy	Unfolded protein response ER stress pathway-CALR, DDIT3, DNAJC3, EIF2AK3, HSP90B1, HSPA5, XBP1 all down LXR/RXR activation FXR/RXR activation Acute phase response signaling	XBP1 Tunicamycin ERN1 RORC RORA	NRF2-mediated oxidative stress response, acyl-coA hydrolysis, ubiquinol-10 biosynthesis, palmitate biosynthesis I (fatty acid synthase up), fatty acid biosynthesis Initiation II(same from palmitate pathway)	NAD Salvage Pathway II Cholesterol Biosynthesis I Cholesterol Biosynthesis II (via 24,25-dihydrolanosterol) Cholesterol Biosynthesis III (via Desmosterol) TWEAK signaling	HNF4A Methylprednisolone miR-155-5p (miRNAs w/seed UAAUGCU) PML DMD
9 mo 1 Gy	Role of JAK2 in hormone-like cytokine signaling-IRS2 (insulin receptor substrate 2), SOCS2 (suppressor of cytokine signaling), SOCS3 all up Acute phase response signaling-IL1R1, SAA1 * (serum amyloid A1), SOCS2, SOCS3, all up TF (transferrin) down Sirtuin signaling pathway-ARNTL, CDH1, GADD45G, MT-ND4, MT-ND5 all up, MYCN (MYCN proto-oncogene, bHLH TF) down IGF-1 signaling-IGFBP1, IRS2, SOCS2, SOC3 all up IL-9 signaling-IRS2, SOCS2, SOCS3 all up	RORC Dexamethasone IL1B RORA tretinoin	PXR/RXR signaling-CYP2A6 down, CYP2B6 down, IGFBP1 up, LXR/RXR-IL1R1 up, SAA1 * up, TF down, FXR/RXR-SAA1 * up, SLC22A7 up, TF down Phosphatidylethanolamine biosynthesis II (choline kinase alpha up)	Glycine Betaine Degradation Clathrin-mediated endocytosis signaling Methionine salvage II (mammalian) L-serine degradation Caveolar-mediated endocytosis signaling	Diethylnitrosamine miR-155-3p (miRNAs w/seed UCCUACC) RORA TP53 NCOA6	Sirtuin signaling pathway, superoxide radicals degradation
12 mo 1 Gy	Mitochondrial dysfunction VDR/RXR activation-EP300, FOXO1, GADD45A, NCOR2, and PPARD all down, HR up B cell receptor signaling-9 molecules exported Estrogen receptor signaling-EP300, HNRNPD, NCOR2, RRAS, SPEN, TAF15, TAF4B all down Acute phase response signaling-IL1R1, IL6R, MAP3K5, RRAS, SAA1 *, SAA2-SAA4, SERPINA3, SOCS3 all down	ST1926 IL3 EPOR Lipopolysaccharide IL1B	Sirtuin signaling, mTOR	Stearate Biosynthesis I (animals) Acyl-CoA hydrolysis Acetone Degradation I (to methylglyoxal) Clathrin-mediated endocytosis signaling Sirtuin signaling pathway	NKX2-2-AS1 HNF4A Pirinixic acid Ciprofibrate di(2-ethylhexyl) phthalate	mitochondrial L-carnitine shuttle pathway
1 mo 3 Gy	IL-17A signaling in fibroblasts-CEBPB (CCAAT enhancer binding protein beta) up; CEBPD (delta) up; JUN (Jun proto-oncogene) up; LCN2 (lipocalin 2) down Glucocorticoid receptor signaling-AR (androgen receptor) up; CDKN1A (cyclin dependent kinase inhibitor 1A) up; CEBPB up; DUSP1 (dual specificity phosphatase 1) up; FKBP5 (FK506 binding protein 5) up; JUN up; TSC22D3 (TSC22 domain family member 3) up Acute phase response signaling-APCS (amyloid P component, serum) down; CEBPB up; IL6R (interleukin 6 receptor) up; JUN up; SAA1 (serum amyloid A1) down JAK/Stat Signaling-CDKN1A (cyclin dependent kinase inhibitor 1A) up; CEBPB up; Jun up Hepatic Fibrosis/Hepatic Stellate Cell Activation-COL15A1 (collagen type XV alpha 1 chain) down; COL25A1 (collagen type XXV alpha chain) down; CTGF (connective tissue growth factor) up, IL6R up	TNF IL1B IFNG Glucocorticoid dexamethasone	Sumoylation pathway	Remodeling of epithelial adherns junctions Clathrin-mediated endocytosis signaling Systemic lupus erythematosus signaling Fcy receptor-mediated phagocytosis in macrophages and monocytes Caveolar-mediated endocytosis signaling	HNF4A SREBF1 TLE3 miR-30c-5p (and other miRNAs w/seed GUAAACA) COMMD1	Insulin receptor signaling, sirtuin signaling pathway, mTOR signaling, PPAR signaling, PI3K/AKT signaling, ceramide signaling (sphingomyelin phosphodiesterase 4 (up)), PTEN Signaling
2 mo 3 Gy	EIF2 signaling Regulation of eIF4 and p70S6K signaling mTOR signaling Unfolded protein response NRF2-mediated oxidative stress response	MLXIPL YAP1 Tunicamycin XBP1 MYCN	Sirtuin signaling pathway, ceramide signaling, ER stress pathway	Acute phase response signaling Clathrin-mediated endocytosis signaling tRNA charging RhoGDI signaling Death Receptor signaling	Monobutyl phthalate HNF4A CST5 OGA 2,4,5,2′,4′,5′-heachlorobiphenyl
4 mo 3 Gy	Oxidative phosphorylation Mito dysfunction Sirtuin signaling pathway-FOXO1, MT-CYB, MT-ND2, MT-ND4, MT-ND5, PPARGC1A all up, RRP9 down Unfolded protein response-HSPA5, Hspa1b, SYVN1 all down Granzyme B signaling-ENDOG (endonuclease G), LMNB2 (lamin B2) both down PXR/RXR activation-CYP2C8, FOXO1, PPARGC1A all up FXR/RXR activation-FOXO1 up, PPARGC1A up, SAA1 * down	IL1B THBS4 STAT3 ALKBH1 NSUN3		JAK/Stat signaling IL-7 signaling pathway Reelin Signaling in Neurons Clathrin-mediated endocytosis signaling Systemic lupus erythematosus signaling	HNF4A Glucagon SREBF1 Insulin PPARGC1B	Sirtuin signaling, sphigosine-1-phosphate signaling, ubiquinol-10 biosynthesis (coenzyme Q3, methyltransferase up & cytochrome P450 family 46 subfamily A member 1 (down))
9 mo 3 Gy	Mito dysfunction Oxidative phosphorylation IL-7 signaling pathway-IGHG1, Ighg2b, Ighg2c, MYC all up, JUN down Sirtuin signaling pathway-HIST1H4J & JUN down, MT-ND2, MT-ND4, MT-ND6, MYC, NDUFB4 all up LPS/IL-1 mediated inhibition of RXR function-ALAS1, CYP2A6, CYP7A1, GSTA5, Sult1d1 all up and JUN down	Lipopolysaccharide RORC NR1I2 RORA Cadmium chloride		Actin cytoskeleton signaling Acute phase response signaling Integrin signaling Signaling by Rho Family GTPases Remodeling of Epithelial Adherens Junctions	Desmopressin HNF4A Levodopa PPARA Gcg	Sirtuin signaling pathway, sphingosine-1-phosphate signaling
12 mo 3 Gy	Aryl hydrocarbon receptor signaling-DCT (dopachrome tautomerase) up, EP300, NCROR2, NFIA, NFIC, TP53 all down RAR activation-CYP26A1 up, ARID1A, EP300, NCOR2, ZBTB16 all down Iron homeostasis signaling pathway-ATP6V0C, EPAS1, IL6R all down, TFRC up Superpathway of cholesterol biosynthesis-DHCR7 down, FDPS up Hereditary breast cancer signaling-ARID1A, EP300, TP53 all down, UBC (ubiquitin) up	Diethylnitrosamine ACOX1 Hydrogen peroxide Pirinixic acid TAS-103	PPARalpha/RXRalpha-BCL3, EP300, NCOR2 all down, Cyp2c54 up, sumoylation pathway	Tight Junction Signaling RhoGDI Signaling Huntington’s Disease Signaling Mechanisms of Viral Exit from Host cells LXR/RXR activation	HNF4A CST5 SREBF1 D-glucose IPMK