. 2016 Mar 14;7:33. doi: 10.3389/fphys.2016.00033

Table 2.

The effect of an environmental challenge on postnatal phenotype.

Manipulation	Species	Treated from	Birth and postnatal body weight	Postnatal age at study	Cohort examined	Postnatal phenotype	References
TOTAL CALORIE RESTRICTION
30%UN^ˆ	Rat	D1-21	↓birth and postnatal weight Vickers et al., 2000 or catch-up growth Riviere et al., 2005	4 months	Male offspring	↑blood pressure, food intake, plasma insulin, leptin, Ang II, aldosterone and adiposity ↓relative kidney and liver weights ↓nephron number	Vickers et al., 2000; Riviere et al., 2005
			↓birth and postnatal weight^#	4 months	Male offspring	Glucose intolerant Altered hypothalamic-regulatory system (POMC neurons sensitivity) ↑food intake, adiposity, plasma and adipose leptin, plasma corticosterone	Breton et al., 2009; Lukaszewski et al., 2011, 2013
35%UN	Rat	D15-20	↓birth weight followed by catch-up growth	4 months	Male offspring	↑plasma FFA ↓hepatic Akt-1, Akt-2 and PKCζ expression and skeletal muscle GLUT4 expression	Camm et al., 2011
50%UN	Rat	D1-D22	↓birth weight followed by catch-up growth at 3 weeks but normalized by 5 months	Birth to ~5 months	Male and female offspring	2 days: ↓plasma leptin and insulin Early onset of puberty ↓plasma progesterone levels (females only)	Sloboda et al., 2009; Smith et al., 2014
						5 months: ↑plasma leptin and insulin, plasma lipase and cholesterol (males only), adiposity, absolute and relative liver weight ↓plasma IGF-1, IGFBP3, hepatic IGFBP1 and IGFBP3 expression
50%UN	Rat	D1-weaning	↓birth and postnatal weight at 3 weeks and 5 months	Birth to ~5 months	Male and female offspring	Early onset of puberty 5 months: ↑plasma leptin and insulin, adiposity, insulin resistant	Sloboda et al., 2009
50%UN^ˆ	Rat	D10-21	↓birth weight followed by catch-up growth and ↑weight at 9–10 months	1 day to 10 months	Female and/or male offspring	1 day: ↓plasma glucose, insulin and triglyceride ↑lean mass ↓adipose FAS and HSL and ↑PPARγ₂ expression ↓hepatic PPARα and PPARγ and ↑LPL, FAS and CRP expression ↓renal developmental and proliferation/apoptotic proteins (GFRAα1 and pERK1/2) Altered vascular ECM composition ↓branching angiogenesis, VEGF expression but ↑eNOS in microvessels ↓plasma leptin and E₂, ↑LH ↑ovarian Ob-Rb, ↓ERα receptor and steroidogenic enzymes (HSD3B1, HSD3B2) ↓hypothalamic GnRH and ↑Ob-Rb and ERα receptor expression (females only)	Desai et al., 2005b, 2007a,b, 2008; Khorram et al., 2007a,b, 2010, 2015; Magee et al., 2008; Henry et al., 2010; Tafti et al., 2011; Fukami et al., 2012; Alves et al., 2015
						3 weeks: ↑adipocyte cell size and renal MEK1/2 expression ↓nephron number
50%UN^ˆ	Rat	D10-21	↓birth weight followed by catch-up growth and ↑weight at 9–10 months	1 day to 10 months	Female and/or male offspring	4–8 weeks: ↑food intake related to impaired leptin signaling and appetite-regulatory pathways in the hypothalamus (Ob-Rb and STAT3, assessed in males)	Desai et al., 2005b, 2007a,b, 2008; Khorram et al., 2007a,b, 2010, 2015; Magee et al., 2008; Henry et al., 2010; Tafti et al., 2011; Fukami et al., 2012; Alves et al., 2015
						2 months: ↑blood pressure, altered vascular ECM composition
						3–4 months: ↑blood pressure and VEGF expression in vasculature Alterations in food preferences and behavioral-neurochemical responses to sweet food (↑TH content in OFC and/or NAcc)
						9 months: glucose intolerant, ↑plasma glucose, insulin, triglyceride and CRP ↑adiposity (↑adipocyte cell size) ↓lean mass and relative heart, kidney, adrenal, liver, lung and brain weights ↑adipose SREBP1C, PPARγ₂, FAS, HSL, LPL expression ↓hepatic PPARα and PPARγ and ↑SREBP1, LPL and FAS expression ↑adrenal leptin expression and altered steroidogenic enzyme expression (males: ↑CYP11A1, CYP11B2, HSD1, Ob-Ra/Ob-Rb and GCR, ↓CYP17A1 expression; females: ↑CYP11A1, ACTH-R and Ob-Ra, ↓GR and CYP17A1 expression)
						10 months: ↓plasma insulin, altered appetite-regulatory pathways in the hypothalamus (females only: ↑NPY, AgRP and pAMPK/AMPK and ↓POMC) Estrous cyclicity disrupted with ↓number of corpora lutea and small follicles ↑plasma LH, FSH and T and ↓E₂ ↑E₂ ovarian receptor, ↓Ob-Rb, LH receptor and steroidogeneic enzymes (CYP11A1, HSD-3β1, CYP19A1) ↑hypothalamic GnRH and ↓Ob-Rb and ERα receptors (females only)
50%UN	Rat	D10-weaning	↓birth weight followed by catch-up growth and ↑weight at 9 months	1 day, 3 weeks and 9 months	Male and female offspring	1 day: ↑plasma ghrelin and ↓plasma leptin, glucose and triglyceride	Desai et al., 2005a,b, 2007b
						3 weeks: ↓adiposity, pancreas and liver weights, plasma glucose and insulin ↑lean mass, relative lung and brain weight and plasma cholesterol
						4–8 weeks: ↑food intake
						9 months: Glucose intolerant, ↑plasma ghrelin, glucose, cholesterol ↓relative heart and kidney weights and plasma insulin
50%UN	Rat	D14-weaning	↓birth weight in male offspring and ↓weight in both male and female offspring at 3 weeks	Birth to 1 month	Male and female offspring	3 weeks: Delayed puberty onset ↓plasma leptin, adiposity, testicular and ovarian weights ↓plasma FSH (males only) Altered plasma FSH (males↓; females↑) ↑UCP1 expression and altered development of gonadal WAT (favored acquisition of a brown-like phenotype, males only)	Leonhardt et al., 2003; Delahaye et al., 2010
50%UN	Rat	D14-weaning	↓postnatal weight	Birth to 8 months	Male offspring	1 day-2 weeks: ↓plasma CBG and leptin	Leonhardt et al., 2002; Lesage et al., 2002b; Sebaai et al., 2002a,b, 2004; Vieau et al., 2007; Delahaye et al., 2008; Coupe et al., 2009; Laborie et al., 2011; Wattez et al., 2014
						2 weeks-1 month: ↓hypothalamic POMC expression and delayed BDNF expression and cell proliferation in the hippocampus and hypothalamus
						3–4 months: ↓plasma CBG, ↑plasma aldosterone and VP ↓absolute and ↑relative adrenal weight, ↓absolute kidney, thymus and liver weights Altered adrenal and kidney ANP receptor expression ↑adrenal POMC expression
						3 weeks, 4 and 8 months: altered MR, GR expression in hippocampus, ↑plasma corticosterone
						6 months: ↑blood pressure, plasma leptin, impaired glucose tolerance, increased food intake ↓locomotor activity
						8 months: ↓plasma catecholamines ↑adrenal POMC, hypothalamic VP and adrenal GR and PC2 expression Alterations in adrenal medulla noradrenergic chromaffin cell aggregation and cholinergic innervation ↓expression of genes involved in cytoskeleton remodeling and vesicle trafficking in adrenal medulla
10–30%UN	Guinea pig	-D28-birth	↓birth and postnatal weight (males only) ↔female offspring	Birth to 4 months	Male and female offspring	3–4 months: ↑plasma cholesterol and insulin, blood pressure, adiposity, adrenal weight and food intake ↓glucose tolerance and lean mass (males only)	Kind et al., 1999, 2002, 2003
LOW-PROTEIN DIET
8% vs. 20% protein	Rat	D1-21	↔birth weight ↓postnatal weight at 2 months	Up to 6 months	Male offspring	↑blood pressure ↓mesenteric artery vasodilatory response	Brawley et al., 2003
8% vs. 20% protein	Rat	D1-21	↔birth weight ↓postnatal growth rate	1, 3 and/or 6 months	Male and female offspring	1 and/or 3 months (males only at 3 months): ↑blood pressure ↑hepatic PPARα, GR, Acyl-CoA expression (related to changes in DNA methylation and/or histone modifications) ↑cardiac PPARα and CPT-1 mRNA expression (related to changes in PPARα DNA methylation)	Lillycrop et al., 2005, 2007, 2008; Torrens et al., 2006; Burdge et al., 2007; Elmes et al., 2007, 2008; Rodford et al., 2008; Hoile et al., 2011; Slater-Jefferies et al., 2011
8% vs. 20% protein	Rat	D1-21	↔birth weight ↓postnatal growth rate	1, 3 and/or 6 months	Male and female offspring	Impaired mesenteric artery vasodilatory response, ↑aorta eNOS expression (males only) ↓mesenteric artery smooth muscle content ↓hepatic HO-1 expression (males only)	Lillycrop et al., 2005, 2007, 2008; Torrens et al., 2006; Burdge et al., 2007; Elmes et al., 2007, 2008; Rodford et al., 2008; Hoile et al., 2011; Slater-Jefferies et al., 2011
						6 months: Impaired left ventricular developed pressure recovery during reperfusion following myocardial ischaemia (males only)
					Male offspring	3 months: Altered hepatic transcriptome (e.g. ion transport, developmental processes, response to oxidative species and steroid hormones) ↓hepatic GR1₁₀ and PPARα DNA methylation, ↑hepatic PEPCK expression ↑blood pressure Impaired mesenteric artery vasodilatory response ↓aorta eNOS expression
					Female offspring	2.5 months: ↑plasma glucose, altered hepatic transcriptome
8% vs. 20% protein	Rat	D1-21	↔birth weight ↓postnatal growth rate	~1 to 6.5 months	Male and female offspring, F2 generation	↑blood pressure in male and female F2 offspring at 3.5 months Impaired mesenteric artery vasodilatory response at 3.5 and 6.5 months in male F2 offspring (female offspring not assessed)	Torrens et al., 2008; Hoile et al., 2011
					Male offspring, F2 generation	↓hepatic GR1₁₀ and PPARα DNA methylation and ↑hepatic PEPCK expression
					Female offspring, F2 generation	↑plasma glucose and altered hepatic transcriptome
8% vs. 20% protein	Rat	D1-21	↔birth weight ↓postnatal growth rate	2.5 months	Female offspring, F3 generation	Altered hepatic transcriptome	Hoile et al., 2011
6% vs. 20% protein	Rat	D1-21	↓birth and postnatal weight	4 months	Female offspring	↑blood pressure and plasma testosterone ↓plasma oestradiol and aorta ERα expression	Sathishkumar et al., 2012
			Not reported	6 months	Female offspring	↑blood pressure, plasma testosterone and vascular Agtr1/Agtr2 ratio Enhanced mesenteric artery contractile response to Ang II	Sathishkumar et al., 2015
			↓birth and postnatal weight	12 months	Female offspring	↓estrous cyclicity ↑blood pressure Greater hypotensive and hypertensive response ↑mesenteric artery contractility and ↓vasodilatory responses ↓NO-mediated vascular responsivity	Sathishkumar et al., 2009
		D4-21	↓birth weight followed by catch-up growth	4 months	Male offspring	Glucose intolerant though ↑plasma insulin during glucose challenge ↑skeletal muscle IR and AS160 expression Defective phosphorylation of IRS-1 and GLUT4 translocation	Blesson et al., 2014
5% vs. 19% protein	Rat	D1-22	↓birth weight followed by catch-up growth	1 month	Male and female offspring	↑hepatic and muscle glycogen ↓hepatic oxygen uptake, mitochondrial swelling and lipid peroxidation ↑hepatic ADP/O ratio	Moraes et al., 2014
HIGH-CALORIE DIETS
5.4x fat	Mouse	-D56-weaning	↑postnatal weight at 3 weeks	3 weeks and ~4.5 months	Male and female offspring	3 weeks: ↑plasma triglycerides (males only) ↑liver weight and lipid accumulation, ↓fatty acid oxidation genes	Mazzucco et al., 2016
						4.5 months: ↑liver FFA (females only), liver weight and lipid accumulation, ↓CPT1 (males only) and ACO expression
12x fat	Mouse	-D28-weaning	↑postnatal weight at 6 months	6 and 12 months	Female offspring	6 months: ↑plasma glucose, ↓bone mineral density	Liang et al., 2009b
						12 months: ↑plasma insulin and glucose, blood pressure, trabecular spacing, ↓trabecular connectivity density
4.8x fat	Rat	D1-weaning	↓birth weight followed by catch-up growth and ↑weight at 3 weeks and 5 months	Birth to ~5 months	Male and/or female offspring	2 days: ↓plasma leptin and insulin	Howie et al., 2009, 2013; Sloboda et al., 2009; Connor et al., 2010, 2012; Smith et al., 2014
						3 weeks: ↑plasma insulin Early onset of puberty
						4–5 months: ↑plasma leptin and insulin, adiposity, bone mineral content, absolute liver weight, insulin resistant ↓plasma IGF-1, IGFBP3, corticosterone (males only) ↓hepatic IGFBP1 and IGFBP3 expression, ↑plasma lipase and cholesterol (males only) ↑pancreatic INS1, INS2, IRS1, IRS2, IL-1R1 and CD68 (males only) ↑plasma progesterone levels and prolonged and persistent oestrus ↓testes: body weight ratio and ↑adrenal ACTH-R
4.8x fat	Rat	-D78-weaning	↓birth and postnatal weight at 3 weeks	Birth to ~5 months	Male and/or female offspring	3 weeks: ↑plasma insulin and food intake (to 2 months) Early onset of puberty ↑plasma progesterone	Howie et al., 2009, 2013; Sloboda et al., 2009; Connor et al., 2010
						5 months: ↑bone mineral content ↑pancreatic STAT3, TNF-α, CD68 and ↓PI3K expression
2.5x fat	Rat	D1-weaning	↓birth weight followed by catch-up growth and ↑weight in adulthood	Birth to ~5 months	Male and female offspring	2 days: ↓plasma leptin and insulin Impaired hepatic proliferation (related to ↑expression and ↓DNA methylation of Cdkn1α, males only)	Dudley et al., 2011
						1 month: ↓liver and liver: brain weight ratio (males only)
Excess of 20% fructose in drinking water	Rat	D1-P10	↑birth weight ↔postnatal weight at 10 days	Birth to 10 days	Male and female offspring	10 days: ↓absolute and relative liver and kidney weight ↑stomach content of leptin and ↓plasma insulin ↑hepatic triglycerides and SREBP1c expression	Vickers et al., 2011; Clayton et al., 2015
Excess of 20% fructose in drinking water	Rat	D1-P10	↑birth weight ↔postnatal weight at 10 days	Birth to 10 days	Male and female offspring	↓hepatic SIRT1 expression (females only) Alterations in the expression of genes regulating beta oxidation and the inflammasome, particularly in males	Vickers et al., 2011; Clayton et al., 2015
Excess of 10% fructose in drinking water	Rat	D1-D21	↔postnatal weight	3 months	Male and female offspring	↑retroperiotoneal adiponectin, FTO, MCP1 and TLR4 mRNA	Lineker et al., 2015
HYPOXIA
12% hypoxia	Mouse	D14-19	↓birth weight of male and female offspring followed by catch-up growth	~2.5 months	Male and female offspring	Impaired mesenteric artery vasodilatory response and ↓elastin content in aorta ↑mesenteric artery stiffness and collagen content in aorta (males only)	Walton et al., 2015
13% hypoxia	Rat	D6-D20	↔birth weight	4 months	Male offspring	↓vasodilatory response of femoral arteries ↑myocardial contractility, LF/HF heart variability ratio, baroreflex gain and maximal and minimal heart rates	Giussani et al., 2012; Kane et al., 2013
IRON RESTRICTION
Iron restriction	Rat	-D21/28-birth	↓birth and postnatal weight but greater growth rate between postnatal days 20 and 40	3 weeks and ~1.5 months	Not specified	3 weeks: ↓blood pressure, ↑relative heart and kidney weights	Crowe et al., 1995
						1.5 months: ↑blood pressure and relative heart and kidney weights
Iron restriction	Rat	-D7-birth	↓birth and postnatal weight	3, 16, and 18 months	Male and female offspring	3 months: ↑blood pressure and serum ACE, ↓serum triglyceride	Lewis et al., 2001c, 2002
						16 months: ↑blood pressure and relative heart and kidney weights, glucose tolerance, ↓serum triglycerides
UTERINE SUBSTRATE SUPPLY
Uterine ligation^ˆ	Rat	D18	↓birth weight followed by catch-up growth (catch-up growth females only)	Birth to 18 months	Male and female offspring	↔blood pressure or nephron number ↔vascular stiffness or reactivity (males only) ↔age of onset of puberty	Wlodek et al., 2007, 2008; Siebel et al., 2008, 2010; Wadley et al., 2008, 2013; Moritz et al., 2009; Mazzuca et al., 2010, 2012; Black et al., 2012; Lauritz et al., 2012; Tare et al., 2012; Gallo et al., 2012a,b; Master et al., 2014; Romano et al., 2014, 2015; Tran et al., 2015
Uterine ligation^†	Rat	D18	↓birth weight and postnatal weight	Birth to 18 months	Male and female offspring	↑blood pressure and left ventricular mass, ↓nephron number ↓femur length, trabecular and cortical bone mineral contents, trabecular density and bone geometry measures Delayed onset of puberty, ↓plasma leptin levels at puberty onset and altered concentrations of sex steroids	Wlodek et al., 2007, 2008; Siebel et al., 2008, 2010; Wadley et al., 2008, 2013; Moritz et al., 2009; Mazzuca et al., 2010, 2012; Black et al., 2012; Gallo et al., 2012a,b; Lauritz et al., 2012; Tare et al., 2012; Master et al., 2014; Romano et al., 2014, 2015; Tran et al., 2015
						Female only phenotypes: Glomerular hypertrophy, ↑plasma creatine and renal TGF-β1, MMP-9 and collagen IV expression ↑HOMA and intramuscular triglycerides (6 months), ↓HOMA and improved insulin sensitivity (12 months) ↓relative islet and β-cell mass ↑plasma triglycerides, uterine artery stiffness and proportion of thick collagen fibers and ↓uterine artery relaxation ↑spatial memory Delayed developmental ↓cardiac PGC-1α and GLUT1 expression
						Male only phenotypes: Impaired glucose tolerance and ↓insulin ecretion ↓skeletal muscle glycogen and mitochondrial regulators (PGC-1α, COX IV, mtTFA COX III) ↑mesenteric artery wall stiffness and impaired relaxation, ↓femoral artery relaxation ↑left ventricular Agtr_1A receptor and collagen 3 expression ↓cardiomyocyte number and ↑cardiac Agtr1a, Agtr1b, Blc2 and C-myc expression Altered sensorimotor gating function and enhanced motor function Exacerbated ↓cardiac PGC-1α and mtTFA expression

ACE, angiotensin converting enzyme; Acyl-CoA, acetyl coenzyme A; ACO, acyl-CoA oxidase; AgRP, Agouti-related peptide; Agtr, angiotensin II receptor; ACTHr, adrenocorticotropic hormone receptor; ADP/O, adenosine diphosphate/oxygen ratio; AMPK, activated protein kinase; Ang, angiotensin; Akt, protein kinase B; ANP, atrial natriuretic peptide; AS160, TBC1 domain family member 4; BDNF, brain derived neurotropic factor; Blc2, B-cell lymphoma 2; CBG, corticosterone-binding globulin; CD68, cluster of differentiation 68; Cdkn1α, cyclin-dependent kinase inhibitor 1α; COX, cytochrome oxidase; CPT-1, carnitine palmitoyltransferase I; CRP, c-reactive peptide; CYP, Cytochrome P450; ECM, extracellular matrix; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-regulated protein kinase; ERα, estrogen receptor α; FAS, fatty acid synthase; FFA, free fatty acids; FSH, follicle stimulating hormone; FTO, fat mass and obesity-associated protein; GFRA, growth factor receptor alpha; GLUT, glucose transporter; GnRH, gonadotropin-releasing hormone; GR1₁₀, glucocorticoid receptor 1(10) promoter; GR, glucocorticoid receptor; HO, heme oxygenase; HOMA, homeostasis model assessment; HSD, hydroxysteroid dehyrodenase; HSL, hormone sensitive lipase; HSP, heat shock protein; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; INS, insulin; IR, insulin receptor; IRS, insulin receptor substrate; LF/HF, low/high frequency; LH, luteinizing hormone; LPL, lipoprotein lipase; MCP1, monocyte chemoattractant protein-1; MEK, mitogen-activated protein kinase; MMP, matrix metallopeptidase; MR, mineralocorticoid receptor; MtTFA, mitochondrial transcription factor A; NAcc, nucleus accumbens; NO, nitric oxide; NPY, neuropeptide Y; NT, nitro tyrosine; Ob-Ra, leptin receptor (short); Ob-Rb, leptin receptor (long); OFC, orbitofrontal cortex; P, postnatal; PC2, prohormone-convertase 2; PEPCK, phosphoenolpyruvate carboxykinase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PI3K, phosphoinositol-3 kinase; PKC, protein kinase C; POMC, proopiomelanocortin; PPAR, peroxisome proliferator-activated receptor; SIRT1, sirtuin 1; STAT3, signal transducer and activator of transcription 3; SREBP, sterol regulatory element binding protein; T, testosterone; TGF, transforming growth factor; TH, tyrosine hydroxylase; TLR, toll-like receptor; TNF, tumor-necrosis factor; UCP1, uncoupling protein 1; VEGF, vascular endothelial growth factor; VP, vasopressin; WAT, white adipose tissue.

^ˆ

Cross-fostered to ad libitum control dam,

dams allowed to eat ad libitum post-partum,

^†

offspring cross-fostered to placentally-restricted dam.

Gestational age: mouse ~20 days, rats ~23 days, guinea pigs ~70 days.