Table 1.
Summary of animal and human nutrient and environmental exposures during lactation.
| Programming influence | Author | Species | Breast milk composition | Sex differences | Metabolic outcomes and mechanisms |
|---|---|---|---|---|---|
| Undernutrition | Sadagurski et al. (2014) | Mouse | Not evaluated | Both male and female mice became insulin sensitive at different time points in adulthood (later in females). Males only had reduced beta cell mass and proliferation rate | Reduced body fat and perigonadal adipocyte size, increased lean body weight, lower fasting leptin, increased insulin sensitivity in pups of a crowded litter |
| Lopez-Soldado et al. (2006) | Rat | Triacylglycerol concentration lower in dams with large litters | Males had decreased lumbar and epididymal adipose weights, lower weight, reduced VLDL-TG (adult) | Decreased total weight and adipose weight (males), increased insulin sensitivity in pups of a large litter | |
| Overnutrition | Glavas et al. (2010) | Mouse | Not evaluated | Male rats studied exclusively | Increased body weight, increased fat deposits (visceral, epididymal, retroperitoneal) and hyperleptinemia with hypothalamic leptin resistance. As an adult, insulin resistance and obesity developed when challenged with a high-fat diet |
| Bernardo et al. (2016) | Mouse | Not evaluated | Male mice studied exclusively | Increased body weight and visceral fat, increased liver weight with hyperinsulinemia and hyperglycemia. Impaired insulin signaling in the heart with mild mitochondrial structure abnormalities | |
| Plagemann et al. (1992) | Rat | Not evaluated | Male rats studied exclusively | Increased body weight gain persisting into adulthood, increased systolic blood pressure and elevated basal insulin level | |
| Xiao et al. (2007) | Rat | Not evaluated | Male rats studied exclusively | Increase in body weight, increased food intake, impaired brown adipose tissue thermogenic response to cold stimulus | |
| Rajia et al. (2010) | Rat | Not evaluated | Male rats studied exclusively | Increased weight and white adipose tissue on chow diet in small litter and impaired glucose tolerance and liver fat on adult HFD re-challenge in the small litter offspring | |
| Bei et al. (2015) | Rat | Not evaluated | Male rats studied exclusively | Adult insulin resistance, increased free fatty acid and increased triglycerides levels, increased body weight and white adipose tissue. Impaired insulin signaling with downregulation of GLUT4 receptors in adipose tissue and skeletal muscle | |
| Lewis et al. (1989) | Primate | Not evaluated | Female baboons had increased fat mass and adipocyte volume; overfed males had no weight change but increased fat in visceral and subcutaneous depots | Obese phenotype (female) baboons, potentially mediated by increased adipocyte volume | |
| Lewis et al. (1992) | Primate | Not evaluated | Female baboons studied exclusively | Early increased insulin secretion in response to meals but not at later time points. Early blunted cortisol responses that resolved by 18 weeks of age. Increased weight in females after puberty and no change in fat cell volume | |
| Carbohydrate | Early outcomes: Srinivasan et al. (2000, 2001) | Rat | Not evaluated | Sex differences not analyzed or male rats exclusively studied | Hyperinsulinemia related to increased GLP-1 and GLP-1 receptor mRNA with increased downstream signaling pathway activity; increased activity of protein kinases that mediate insulin secretion in offspring islets; increased insulin biosynthesis with increased PDX1 levels with increased mRNA of factors regulating Pdx1 expression |
| Adult outcomes: Hiremagalur et al. (1993), Aalinkeel et al. (2001), Srinivasan et al. (2013) | HCD, offspring developed increased body, perigonadal fat pad and liver weights; increased liver fat; increased adipocyte size in epididymal tissues and increased lipogenic enzyme activity (Hiremagalur et al. 1993). Offspring also showed increased basal and stimulated insulin levels with underlying increases islet in Glut2 and preproinsulin mRNA, along with upstream factors that regulate preproinsulin transcription (Aalinkeel et al. 2001). Pair feeding after HCD reduced weight gain and serum hormones normalized, however islets remained hypersecretory (Srinivasan et al. 2013) | ||||
| Goran et al. (2017) | Human | Breast milk sugars measured | No effect of infant sex | Breast milk fructose composition at 6 months related to increased infant growth in weight, lean mass and fat mass | |
| Protein | Kucia et al. (2011) | Mouse | Decrease in milk lactose content with high-protein diet | Similar outcomes for males and females | A maternal high-protein diet during lactation showed reduced litter mass linked to decreases in mammary gland mRNA levels with impaired lactation |
| Moura et al. (2002) | Rat | Not evaluated | Sex differences not analyzed | Maternal low-protein diet led to increased offspring plasma insulin and leptin during lactation and decreased during adulthood during a re-challenge protein-free diet | |
| Morimoto et al. (2012) | Rat | Not evaluated | Male rats studied exclusively | Rat offspring with maternal protein-restriction showed increased islet insulin secretion in vitro at weaning but impaired insulin secretion after glucose challenge as adults | |
| Rodrigues et al. (2017) | Rat | Not evaluated | Female rat pups nursed on high-protein cow’s milk developed increased fat, hyperphagia and lower insulin secretion. Males had lower overall body protein | Female rats developed hypoinsulinemia and normoglycemia while males showed unchanged insulin levels and hyperglycemia when nursed on a high-protein cow’s milk diet, potentially mediated by estrogen and prolactin | |
| European Childhood Obesity Trial: Koletzko et al. (2009), Escribano et al. (2012), Weber et al. (2014) | Human | Not evaluated | Analysis adjusted for sex | At age 2 years, infant fed a higher protein diet had increased Wt/L Z-score and increased weight (Koletzko et al. 2009). Increased weight gain velocity and fat mass for first 6 months of life and a higher BMI at 12, but not 24 months for infants given high-protein formula (Escribano et al. 2012). Children given high-protein formula showed increased BMI at 6 years of age and 2.4 times the risk of obesity as compared to the low-protein group (Weber et al. 2014) | |
| Fat | Vogt et al. (2014) | Mouse | Increase in milk glucose and insulin content from dams fed a high-fat diet during lactation | Male mice studied exclusively | A maternal HFD during lactation showed an obese phenotype and impaired glucose tolerance in offspring, mediated by an impairment of axonal projections to the PVH area of the hypothalamus and decreased parasympathetic innervations of the pancreatic beta-cells |
| Liang et al. (2016) | Mouse | Increase in milk triglyceride levels | Male mice studied exclusively | A maternal HFD during lactation showed increased body weight and fat mass in adults with impaired glucose tolerance and insulin sensitivity and an abnormal brown adipose tissue response to cold | |
| Sun et al. (2012) | Rat | Increase in milk leptin and fat content at postnatal day 21 | Similar results in males and females | Rat pups cross-fostered to dams fed HFD during pregnancy and lactation showed greater adiposity with an increase in subcutaneous fat, increased plasma leptin, elevated insulin levels associated with a reduction in STAT3 response to leptin in the hypothalamus | |
| Masuyama and Hiramatsu (2014) | Rat | Not evaluated | Male rats showed an increased leptin surge compared to females | Rat pups cross-fostered to dams fed HFD during lactation showed increased fat mass gain, food intake, glucose intolerance and insulin resistance along with increased mRNA expression of leptin, triglycerides and adiponectin | |
| Fatty acids | Oosting et al. (2010) | Mouse | Increase milk n-3 LC-PUFAs in dams supplemented with n-3 | Male mice studied exclusively | Mice fed an n-3 rich postnatal diet showed a 30% reduction in fat accumulation when challenged in adulthood with a western style diet |
| Korotkova et al. (2002a, b) | Rat | Increase in milk leptin and saturation PUFAs in dams fed EFAD. No difference in leptin level with n-3 and n-6 supplementation | Sex differences not analyzed | Decreased serum leptin levels and leptin mRNA in inguinal white adipose tissues of offspring suckling to dams on EFAD. Pups receiving high-n-3 diet developed lower body weight, inguinal fat pad weight, adipocyte size and serum leptin. Pups receiving increased ratio n-6/n-3 PUFA had increased body weight, inguinal fat pad weight and adipocyte size | |
| Hadley et al. (2017) | Rat | Dams supplemented with a combination ARA and DHA diet had milk with increased ARA and DHA | Male mice studied exclusively | Offspring cross-fostered to dams supplemented with a combination ARA and DHA diet showed increased body weight | |
| Grant et al. (2011) | Primate | Decrease in milk protein, DHA, EPA levels and increase insulin | Sex differences not analyzed | Offspring developed increased body fat and lower lean body mass when maternal diet was supplemented with omega-6. Infant DHA level at 16 weeks had a minor negative association with weight at age 1 and 2 years | |
| Makrides et al. (1999) | Human | Not evaluated | Analysis adjusted for sex | Fish oil supplementation associated with a 0.65 kg/m2 increase in BMI at age 2.5 years | |
| Lauritzen et al. (2005), Asserhøj et al. (2009) | Human | Not evaluated | Analysis adjusted for sex | Maternal erythrocyte DHA level positively associated with offspring BMI and waist circumference (Lauritzen et al. 2005). At age 7 the association no longer remained (Asserhøj et al. 2009) | |
| Helland et al. (2008) | Human | Measured PUFAs in breast milk | Analysis adjusted for sex | Alpha-linoleic acid levels in breast milk sampled at 3-months positively correlated with child BMI at 7 years | |
| Much et al. (2013) | Human | Maternal n-3 supplementation and reduced ARA intake showed a reduced n-6 to n-3 ratio | Analysis adjusted for sex | Breast milk DHA and n-3 fatty acids have a positive relationship with infant body fat subcutaneous to pre-peritoneal ratios at 6 weeks of age | |
| Maternal diabetes | Fahrenkrog et al. (2004) | Rat | Not evaluated | Sex differences not analyzed | Reduced growth rate (weight and length) in offspring of diabetic dams potentially due to malprogramming of the hypothalamus. No difference in plasma insulin, leptin concentrations |
| Plagemann et al. (2002) | Human | Not evaluated | Sex differences not analyzed | Infants of diabetic mothers receiving banked breast milk as supplementation were protected against obesity at 2 years old | |
| Schaefer-Graf et al. (2006) | Human | Not evaluated | Sex differences not analyzed | Offspring of obese mothers with gestational diabetes had a decreased risk of childhood overweight if they were breastfed >3 months | |
| Maternal obesity | Gorski et al. (2006) | Rat | Diet-induced obese dams had higher insulin and decreased total PUFAs | Male rats studied exclusively | Improved insulin sensitivity with maintained obese phenotype in offspring of obese dams fostered to lean dams. Lean dam offspring then given a high-energy diet developed obesity and insulin resistance |
| Bernstein and Hinde (2016) | Primate | Milk growth factors measured | Increased female offspring growth rate with lower milk EGF-receptor | Lower EGF and EGF-receptor in increased weight mothers. Higher EGF and EGF-R associated with increased infant body mass | |
| Mayer-Davis et al. (2006) | Human | Not evaluated, retrospective report | Analysis adjusted for sex | Self-report of exclusive breast feeding to 6 months associated with an odds ratio of 0.75 for overweight in children age 9–14 years | |
| Fields et al. (2017) | Human | Insulin and leptin levels increased with increased BMI | Maternal BMI correlates with higher human breast milk insulin levels for mothers who gave birth to female infants | High-milk leptin associated with decreased infant length and fat mass at 6 months | |
| Stress | Dantzer et al. (2013) | Squirrel | Not evaluated | Sex differences not analyzed | Accelerated offspring postnatal growth rate with maternal physiological stress |
| Hinde et al. (2015) | Primate | Higher milk cortisol with stress. Measured milk fat, protein, sugars | Females more sensitive to milk cortisol in relation to temperament scores | At 1 month, infant growth was highest with higher milk cortisol and milk energy peaked | |
| Hahn-Holbrook et al. (2016) | Human | Cortisol is found in human breast milk | In females, decreased rapid early BMI gain linked to cortisol breast milk levels | Increased milk cortisol associated with lower BMI at 2 years | |
| Smoking | de Oliveira et al. (2010) | Rat | Dams treated with nicotine infusion had milk with higher lactose and energy content. Cotinine levels were similar in milk and plasma | Male rats studied exclusively | Offspring with increased body weight, adipocyte hypertrophy, insulin and leptin levels as adults when exposed to nicotine directly, possibly related to reduced protein in leptin signaling |
| Santos-Silva et al. (2011) | Rat | Smoke-exposed dams showed milk with increased lactose and triglycerides | Male rats studied exclusively | Pups had lower total fat, hyperinsulinemia, hypertriglyceridemia | |
| Santos-Silva et al. (2013) | Rat | Not evaluated | Male rats studied exclusively | In adulthood, pups exposed to smoke had increased total and visceral fat mass, dyslipidemia, increase leptin and adiponectin | |
| Alcohol | Tavares Do Carmo et al. (1999) | Rat | Maternal ethanol intake decreases milk production | Sex differences no analyzed | Decreased body weight and brain weight, higher serum triglyceride/free fatty acid, beta-hydroxy-butyrate levels, decreased plasma glucose in ethanol exposed pups |
| Chen and Nyomba (2004) | Rat | Not evaluated | Male rats studied exclusively | Decreased pup birth weight, increased triglycerides, insulin resistance with ethanol exposure | |
| Nonnutritive sweeteners | Parlee et al. (2014) | Mouse | Not evaluated | In males, decreased fat mass and adipocyte size, improved glucose tolerance with saccharin lactational exposure | Saccharin exposure was linked to initial reduced body weight that persisted in females |
| Environmental toxin | Li et al. (2016) | Rat | Bisphenol AF concentration not measured in milk | Males rats studied exclusively | Bisphenol AF was transferred to pups during lactation and found in the testes with increased testosterone levels, altered gene expression in cell differentiation and meiosis. Decreased body weight of male pups |
| Criswell et al. (2017) | Human | Breast milk PCBs, poly-brominated diphenyl ethers, organochlorine pesticides, β-HCH levels | Results adjusted for child sex | Increased milk β-HCH correlated with reduced infant weight gain at 6 months | |
| Pan et al. (2010) | Human | Breast milk PCBs, pesticides | No effect after co-variate analysis with infant sex | Breast milk chemical levels had no impact on infant growth | |
| Iszatt et al. (2015) | Human | Not evaluated | Sex differences not reported | Postnatal PCB-153 exposure associated with about a 140 g weight deficit at the age of 2 years compared to those with lower exposures |
ARA, arachidonic acid; β-HCH, beta-hexachlorocyclohexane; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; EFAD, essential fatty acid deficient diet; HCD, high-carbohydrate diet; HFD, high-fat diet; LCPUFA, long-chain omega-3 polyunsaturated fatty acids; PCBs, polychlorinated biphenyls; VLDL-TG, very low density lipoprotein triglyceride; BMI, body mass index; EGF, epidermal growth factor; PCB, polychlorinated biphenyl.