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Homage to the ‘H’ in developmental origins of health and disease

Published online by Cambridge University Press:  31 August 2016

C. S. Rosenfeld Open the ORCID record for C. S. Rosenfeld [Opens in a new window]
C. S. Rosenfeld*
Affiliation:
Departments of Biomedical Sciences, University of Missouri, Columbia, MO, USA Departments of Bond Life Sciences Center, University of Missouri, Columbia, MO, USA Thompson Center for Autism and Neurobehavioral Disorders, University of Missouri, Columbia, MO, USA
*
*Address for correspondence: C. S. Rosenfeld, Thompson Center for Autism and Neurobehavioral Disorders, University of Missouri, 440F Bond Life Sciences Center, 1201 E. Rollins Rd., Columbia, MO 65211, USA. (Email rosenfeldc@missouri.edu)
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Abstract

Abundant evidence exists linking maternal and paternal environments from pericopconception through the postnatal period to later risk to offspring diseases. This concept was first articulated by the late Sir David Barker and as such coined the Barker Hypothesis. The term was then mutated to Fetal Origins of Adult Disease and finally broadened to developmental origins of adult health and disease (DOHaD) in recognition that the perinatal environment can shape both health and disease in resulting offspring. Developmental exposure to various factors, including stress, obesity, caloric-rich diets and environmental chemicals can lead to detrimental offspring health outcomes. However, less attention has been paid to date on measures that parents can take to promote the long-term health of their offspring. In essence, have we neglected to consider the ‘H’ in DOHaD? It is the ‘H’ component that should be of primary concern to expecting mothers and fathers and those seeking to have children. While it may not be possible to eliminate exposure to all pernicious factors, prevention/remediation strategies may tip the scale to health rather than disease. By understanding disruptive DOHaD mechanisms, it may also illuminate behavioral modifications that parents can adapt before fertilization and throughout the neonatal period to promote the lifelong health of their male and female offspring. Three possibilities will be explored in the current review: parental exercise, probiotic supplementation and breastfeeding in the case of mothers. The ‘H’ paradigm should be the focus going forward as a healthy start can indeed last a lifetime.

Keywords

exercisebreastfeedingmicrobiomeobesityprobiotics

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Type
Review
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Journal of Developmental Origins of Health and Disease , Volume 8 , Issue 1 , February 2017 , pp. 8 - 29
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Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2016 

Introduction

It has been long recognized that the in utero stamp can lead to longstanding health consequences for male and female offspring.Reference Chow and Lee 1 – Reference Buklijas 3 The well-known Cambridge scientists, Robert McCance and Elsie Widdowson, performed pioneering work that showed the early environment, especially nutrition, could impact pre- and post-natal growth and later risk for adult disease.Reference Buklijas 3 Subsequently, Chow and LeeReference Chow and Lee 1 reported stunted growth in rat offspring born to dams fed an energy restricted diet during gestation. Roeder and ChowReference Roeder and Chow 2 then proposed that maternal undernutrition during pregnancy may result in permanent health consequences in resulting offspring. The late Sir David Barker formalized the concept that the genesis of many non-communicable diseases may trace their origins back to the embryonic/perinatal period, resulting in the ‘Barker Hypothesis’.Reference Barker 4 , Reference Barker 5 The term was then changed to fetal origin of adult disease. However, the final agreed upon terminology is developmental origins of health and disease (DOHaD). This phrase introduces the notion that the perinatal environment can for better or worse shape later offspring health and disease outcomes. Thus, the track to a healthy lifespan may also begin during this vulnerable period.

The DOHaD model has gained greater currency due to the escalating data across various disciplines.Reference Barker 4 , Reference Barouki, Gluckman, Grandjean, Hanson and Heindel 6 – Reference Walker and Ho 13 It is also increasingly becoming apparent that the environmental state of both the mother and father can underpin later diseases in offspring, even those who appear healthy at birth.Reference Rando 14 – Reference Rodgers, Morgan, Leu and Bale 26 Such intrinsic and extrinsic factors in animal models and humans include exposure to endocrine disrupting chemicals, such as bisphenol A, phthalates, heavy metals, stress, obesity, high fat/high caloric diets, metabolic status and starvation conditions to provide a few examples. It is also clear that in general, males may be at greater risk for later disorders, including those of the cardiovascular and neurological systems, than females.Reference Gilbert and Nijland 27 – Reference Dasinger and Alexander 30

Overall, less attention has been devoted to maternal and paternal factors that promote the long-term health of males and females. Even though the concept has been extended to include health, the ‘H’ factor has been for the most part overlooked. Yet, good habits that promote offspring health may be able to mitigate negative perinatal influences. In this review, we will consider three such possibilities: parental exercise, probiotic supplementation and breastfeeding in the case of mothers.

Parental exercise

Maternal exercise and offspring metabolic phenotypes

Maternal exercise either before conception or during gestation might confer later health benefits for male and female offspring and may even be able to compensate for suboptimal uterine environments. The effects of maternal exercise on several offspring trajectories will be considered: cardiometabolic, growth, neurobehavioral and other physiological responses.

There are currently conflicting reports as to whether maternal exercise can improve offspring cardiovascular function with most, however, suggesting positive benefits.Reference Blaize, Pearson and Newcomer 31 Table 1 summarizes the recent animal studies, and provides further details on sex differences and variation observed in lean (control) v . obese exercised dams, where appropriate. In pigs, maternal exercise during pregnancy results in enhanced endothelium-dependent vaso-relaxation response in the thoracic aorta of newborn female offspring.Reference Newcomer, Taheripour and Bahls 32 Adult male and female pigs derived from pregnant sows subjected to exercise during pregnancy show decrease vascular smooth muscle responsiveness when challenged with an exogenous nitric oxide donor.Reference Bahls, Sheldon and Taheripour 33 Conversely, maternal voluntary wheel running during pregnancy does not affect vascular function or voluntary activity in Sprague-Dawley male and female rat offspring.Reference Blaize, Breslin and Donkin 34

Table 1

Animal model studies showing beneficial effects of maternal or paternal changes on offspring DOHaD outcomes

Several rodent studies indicate that maternal exercise before and/or during gestation improves glucose homeostasis,Reference Raipuria, Bahari and Morris 35 , Reference Carter, Qi, De Cabo and Pearson 36 and insulin sensitivityReference Carter, Qi, De Cabo and Pearson 36 and decreases leptin concentrations in offspring.Reference Vega, Reyes-Castro and Bautista 37 Long lasting changes in the musculoskeletal system and adiposity are observed in Wistar rat offspring, especially in males, of exercised dams.Reference Rosa, Blair and Vickers 38 Such changes include lower bone mineral density, increase circulating concentrations of undercarboxylated osteocalcin and greater percentage of total fat but lower percentage of lean fat compared with controls. The beneficial metabolic effects in offspring of exercised dams may be due to gene expression changes in skeletal muscle, such as decrease Il6 (an inflammatory cytokine secreted by T-lymphocytes and macrophages),Reference Wasinski, Bacurau and Estrela 39 increase peptide Pyy (a peptide released from the ileum and colon in response to feeding),Reference Wasinski, Bacurau and Estrela 39 and decrease hypermethylation/increased expression of Pgc1a (a transcriptional co-activator regulating many genes involved in energy metabolism).Reference Laker, Lillard and Okutsu 40

Maternal exercise may also be able to alleviate the effects of high fat diet (HFD) feeding to rodent dams during gestation or post-weaned offspring. Male offspring born to dams that exercised during gestation are protected against HFD-induced hepatic steatosis.Reference Sheldon, Nicole Blaize and Fletcher 41 In female mice, exercise before and during pregnancy combats the effects of maternal HFD on later offspring metabolic parameters, including reversing glucose intolerance, stabilized circulating insulin concentrations, and decreasing adiposity and weight gain.Reference Wasinski, Bacurau and Estrela 39 , Reference Stanford, Lee and Getchell 42 Similarly, rat offspring born to dams fed a HFD but allowed to exercise during pregnancy show improved insulin/glucose metabolism with the effects more pronounced in male v. female offspring.Reference Raipuria, Bahari and Morris 35 A maternal low protein diet fed to rats results in decreased resting oxygen consumption and growth rate of offspring, but these effects are attenuated in dams subjected to physical training.Reference Amorim, dos Santos and Hirabara 43

Although the rodent studies suggest that maternal exercise may confer positive benefits on offspring metabolism, it is not clear whether similar outcomes can be replicated in humans. The handful of studies to date has yielded mixed findings. Table 2 summarizes the current human epidemiological studies or meta-analyses examining the effects of maternal exercise, probiotic supplementation and breastfeeding (the latter two are discussed below) on offspring DOHaD outcomes. Male and female offspring of mothers who exercised during pregnancy show lower birth growth rates and reduce umbilical cord concentrations of serum IGF-1 (growth promoting factor, especially in children).Reference Hopkins, Baldi, Cutfield, McCowan and Hofman 44 In women, vigorous exercise before pregnancy increases endothelial progenitor cells in umbilical cord blood, which could improve offspring cardiovascular function.Reference Onoyama, Qiu and Low 45 Lower toddler weights and weight-for-height z-scores are associated with mothers who engaged in increased leisure-time physical activity during pregnancy.Reference Mattran, Mudd, Rudey and Kelly 46 In contrast, another study reported that muscular fitness of mothers is associated with increase offspring birth weight.Reference Bisson, Almeras and Plaisance 47 Additional studies with larger sample sizes of pregnant women are needed before any definitive conclusions can be drawn. One such ongoing study that might be enlightening is currently underway in Auckland, New Zealand and being called the ‘Improving Maternal and Progeny Risks of Obesity Via Exercise’ (IMPROVE).Reference Seneviratne, Parry and McCowan 48

Table 2

Human epidemiological studies or meta-analyses showing beneficial effects of maternal changes on offspring DOHaD outcomes

Maternal exercise and offspring behavioral and reproductive phenotypes

In several rodent studies, maternal exercise is associated with increased offspring learning and memory abilityReference Dayi, Agilkaya and Ozbal 49 – Reference Gomes da Silva, de Almeida and Fernandes 52 and reduced anxiety.Reference Aksu, Baykara and Ozbal 53 The cognitive and emotional improvements may be due to maternal exercise-induced increase in neural Bdnf (a neurotrophic factor associated with enhanced learning and memory abilities), especially in the hippocampus and prefrontal cortex,Reference Park, Kim and Eo 51 – Reference Aksu, Baykara and Ozbal 53 , leptin (Lep, a satiety hormone),Reference Dayi, Agilkaya and Ozbal 49 Vegf (an angiogenic protein) in the prefrontal cortex,Reference Aksu, Baykara and Ozbal 53 and c-Fos (a proto-oncogene) expression in the perirhinal cortex.Reference Robinson and Bucci 50 Further, maternal exercise may exert positive effects on brain mitochondrial functionReference Park, Kim and Eo 51 , Reference Marcelino, Longoni and Kudo 54 and neuron cell numbers and viability.Reference Dayi, Agilkaya and Ozbal 49 , Reference Gomes da Silva, de Almeida and Fernandes 52 , Reference Herring, Donath and Yarmolenko 55 Dendritic growth of parietal neurons is blunted in offspring of dams subjected to prenatal restraint stress.Reference Bustamante, Henriquez and Medina 56 However, this neuropathological changed is alleviated in offspring of stressed dams who are allowed to exercise on a voluntary running wheel, further emphasizing the power of maternal exercise to overcome negative periconceptional stimuli. Maternal exercise is insufficient though in fully reversing the brain damage observed in rats subjected to in utero hypoxia-ischemia.Reference Marcelino, de Lemos Rodrigues and Miguel 57 In humans, mothers who had increased leisure activity during pregnancy gave birth to offspring who demonstrated transient improvement in vocabulary score at 15 months of age.Reference Jukic, Lawlor and Juhl 58

In pigs, maternal exercise influences fetal and neonatal ovarian development, as evidenced by increased number of proliferating cells in the cortex, but it is not clear if these early changes alter later fecundity.Reference Kaminski, Grazul-Bilska, Harris, Berg and Vonnahme 59 In addition, maternal exercise may decrease offspring risk of cancer later in life. Rat offspring derived from dams that ran on a running wheel while pregnant demonstrate decreased incidence of developing mammary cancers when later challenged with a carcinogen, N-methyl-N-nitrosourea.Reference Camarillo, Clah and Zheng 60

Paternal exercise and offspring phenotypes

To the author’s knowledge, only two papers to date have considered whether paternal exercise before fertilization impacts offspring outcomes. One report with mice suggests that paternal treadmill exercise improves spatial learning and memory ability of male offspring and upregulates expression of Bdnf and Reelin (a gene that mediates neuronal migration in the developing brain and synaptic plasticity in adults), indicating that this paternal behavior can improve male offspring neurobehavioral function.Reference Yin, Wang and Sun 61 In contrast, another mouse study found that males who exercised 12 weeks before mating gave rise to offspring more vulnerable to deleterious effects induced by a HFD, as exemplified by increased in body weight, adiposity, impaired glucose tolerance and elevated insulin levels.Reference Murashov, Pak and Koury 62 Further, several metabolic genes (Ogt, Oga, Pdk4, H19, Glut4 and Ptpn1) are up-regulated in the skeletal muscle of offspring whose fathers underwent long-term exercise. The sperm of exercised fathers harbors DNA methylation and micro-RNA changes, which may lead to transgenerational propagation of the above metabolic changes. Ostensibly, additional studies are needed to determine whether paternal exercise has positive or negative effects on the next generation. The conflicting results so far may be reconciled in part by the duration and type of exercise regimen, whether the activity is voluntary or involuntary, and offspring parameters analyzed.

Probiotic supplementation

Our understanding of how the gut microbiome influences health and disease outcomes has been addressed in some depth in this past decade. The data increasingly reveal that early disruptions in the gut microbiome can affect various systems, including the gastrointestinal, immunological, nervous, metabolic and cardiovascular. With this in mind, there is an interest as to whether pre- and post-natal supplementation through the maternal diet can attenuate later diseases and promote offspring health. The primary focus of most studies to date has been to determine whether maternal probiotic supplementation with select microbes alters offspring immunological gene expression and immunophenotypes. Current animal findings are summarized in Table 1. Rodent dams and pregnant mothers used in the studies detailed below were not exposed to any other extrinsic factors, besides probiotic supplementation, and were not considered overweight or obese.

Supplementation of Swiss albino female mice before conception and throughout lactation to the probiotic Lactobacillus rhamnosus GG (LGG) results in increased serum IgG, intestinal sIgA, IFN-γ (type II interferon produced by T-lymphocytes) concentration, and enhanced antibody response against hepatitis-B surface antigen in offspring.Reference Himaja, Hemalatha, Narendra Babu and Shujauddin 63 Provisioning of mouse mothers and offspring with a probiotic fermented milk (PFM) comprised of Lactobacillus rhamnosus (MTCC: 5897) leads to several beneficial offspring immunological changes.Reference Saliganti, Kapila and Kapila 64 These include decrease inflammatory markers (TNF-α and MCP-1- in the C-C chemokine family and recruits inflammatory cells to a site of injury/inflammation) and IgE but elevations in serum IgA and IFNγ/IL-4 (stimulates development of Th2 lymphocytes and in turn is produced by this cell type). An earlier study with mice perinatally exposed to LGG yielded some similar but also notable cytokine differences.Reference Blumer, Sel and Virna 65 In this report, TNF-α, IFN-γ, Il-5 (produced by Th2 cells and stimulates development of B-lymphocytes and increases immunoglobulin secretion) and Il10 (an anti-inflammatory cytokine) are decreased in offspring derived from dams provided LGG. Another rat study suggests that maternal probiotic intervention decreases IFN-γ levels, upregulates Muc2 (produced by goblet cells and protein product helps contribute to mucous barrier overlying the intestinal epithelial cells) ileal gene expression in male offspring subjected to maternal separation but increases Il-6 in maternally separated pups.Reference Barouei, Moussavi and Hodgson 66 Maternal probiotic supplementation improves immunological responses and partially alleviates gut dysbiosis in offspring subjected to maternal separation.Reference Barouei, Moussavi and Hodgson 67 Gestational and lactation administration of Lactobacillus plantarum 299v (Lp299v) results in this bacterium colonizing the intestinal tract of the dam and offspring.Reference Fak, Ahrne, Molin, Jeppsson and Westrom 68 The small intestines, pancreas, liver and spleen are larger in day 14 offspring exposed to this maternal probiotic supplement, and this group shows reduced gut permeability, which serves an important barrier in preventing systemic spread of pathogenic organisms. In all, the findings suggest that the maternal probiotic supplementation can affect the gastrointestinal and lymphatic systems. Based on the potential immunomodulatory role, select studies have considered whether maternal probiotic supplementation might be a useful adjuvant to prevent various allergic reactions.

Perinatal exposure of mice to Lactobacillus paracasei NCC2461 through the dam’s drinking water prevents later airway inflammation (decreases eosinophils, reduces levels of Il-5 in respiratory and lymph node samples, and suppresses Il-4 and Il-5 production by cultured splenic cells) when offspring are sensitized with recombinant Bet v 1 followed by aerosol challenge with birch pollen extract.Reference Schabussova, Hufnagl and Tang 69 Supplementation of PFM to mouse mothers during lactation or their weanling offspring reduces allergic signs to ovalbumin, increases the number of intestinal goblet and IgA+ cells, reduces antibodies (IgE and IgG) against ovalbumin, and decreases levels of Il-4 and IFN-γ.Reference Saliganti, Kapila and Kapila 64 Probiotic supplementation to dams from gestation through lactation and weanling mouse offspring increases probiotic fecal counts in offspring by 3 weeks of age.Reference Toomer, Ferguson and Pereira 70 The allergic pathway mediator, Il-13, is decreased but T regulatory cell populations are enhanced with the net effect that this group is protected against hypersensitivity reaction due to peanut allergen exposure. In humans, children of women who received probiotic supplementation while pregnant show reduced incidence of atopic dermatitis,Reference Simpson, Dotterud, Storro, Johnsen and Oien 71 although a follow-up study by this same research group suggested that maternal probiotic administration does not alter the gut microbial composition in children (Table 2).Reference Dotterud, Avershina and Sekelja 72 However, a study with pregnant mice, rats and pigs indicates that maternal probiotic administration of Lactobacillus acidophilus and Bifidobacterium lactis 7 days before vaginal delivery results in transfer of this bacterium to neonates (sex of pups not provided) and at least transiently affects the offspring gut microbial colonies.Reference Buddington, Williams, Kostek, Buddington and Kullen 73

Breastfeeding

Breastfeeding is associated with several potential health benefits for the mother and her offspringReference Schack-Nielsen and Michaelsen 74 , Reference Victora, Bahl and Barros 75 . Besides strengthening the maternal-infant bond, the positive offspring benefits of breastfeeding are likely due to the fact that breast milk contains various nutrients, immune-protective cells and factors (discussed below), hormones and other cytokines. Consequently, breastfeeding may be a primary means to prevent many non-communicable offspring diseases, in particular obesity, and even improve human intelligence, which may thereby reduce poverty and social inequalities.Reference Victora, Bahl and Barros 75 We will consider the potential long-term benefits of breastfeeding on reducing offspring obesity and cardiometabolic disorders, improving the gut-microbiome axis, enhancing immunologic functions, decreasing cancer incidence, and strengthening neurobehavioral responses (summarized in Table 2).

Obesity and cardiometabolic disorders

In the past 30 years, childhood obesity rates have doubled in children and quadrupled in adolescents with current estimates approximating 1/3 of children and adolescents are overweight or obese.Reference Ogden, Carroll, Fryar and Flegal 76 – 78 Accordingly, there is a great deal of interest in early factors that may prevent childhood obesity and metabolic disorders. Breastfeeding may provide some protection against later development of these offspring disorders. In support of this notion, the World Health Organization (WHO) published a report suggesting that breastfeeding may yield a small protective effect against childhood obesity.Reference Cope and Allison 79 Additional confirmatory studies with even larger cohort populations have been published since this initial WHO report.

A meta-analyses of 23 high-quality studies encompassing a total sample size of 1500 participants reported breastfeeding is associated with a 13% pooled reduction in the prevalence of overweight or obesity in progeny.Reference Victora, Bahl and Barros 75 A recent study concluded that the mean body mass index (BMI) decreases from 85 to 65% when infants are breastfed for 4–6 months as opposed to 1–3 months and supplementation with non-breast milk before 4 months of age correlates with an increased BMI, arm circumference, and abdominal circumference at 18 months of age.Reference Temples, Willoughby and Holaday 80 Breastfeeding may even confer protective effects on offspring obesity in children whose mothers experienced pre-gestational diabetes.Reference Feig, Lipscombe, Tomlinson and Blumer 81 Longer duration of breastfeeding may attenuate the risk of obesity in offspring whose mothers experienced excessive gestational weight gain.Reference Zhu, Hernandez and Dong 82

A meta-analyses representing 113 individual studies concluded that increased duration of breastfeeding is associated with a 26% reduction in the likelihood of offspring becoming overweight or obese regardless of parental income status.Reference Horta, Loret de Mola and Victora 83 This report also showed a positive association of breastfeeding and reduced odds of children developing type 2 diabetes. Infant breastfeeding has been inversely associated with adult BMI but positively associated with high-density lipoprotein or the good cholesterol form.Reference Parikh, Hwang and Ingelsson 84 A cohort study from Australia with 2900 pregnant women also suggests breastfeeding reduces later offspring cardiometabolic diseases.Reference Huang, Mori and Beilin 85 In addition, breastfeeding may positively influence cardiorespiratory fitness in children and adolescents.Reference Labayen, Ruiz and Ortega 86 Taken together, breastfeeding may confer protective effects against cardiometabolic diseases in offspring of non-obese and obese mothers.

Gut microbiome and immune effects

Breast milk contains abundant immune-related factors, including agranulocytes (B and T lymphocytes and macrophages), granulocytes (neutrophils), antibodies, especially sIgA, lysozyme (an enzyme that catalyzes the destruction of bacterial cell walls), lactoferrin (antimicrobial factor), IFN-γ, oligosaccharides and other compounds.Reference Hanson 87 , Reference Bridgman, Konya and Azad 88 By testing mice either expressing or devoid of Ig receptor mice, it has been shown that maternal sIgA in breast milk stimulates offspring gut microbiota changes that persist and are amplified at adulthood, and blocks translocation of aerobic bacteria, including the pathogen Ochrobactrum antropi, across the intestines and into draining lymph nodes (Table 1).Reference Rogier, Frantz and Bruno 89 , Reference Rogier, Frantz and Bruno 90 In addition, maternal sIgA alters the intestinal gene expression profile, especially those transcripts associated with enteritis in humans, and alleviates dextran-induced colonic mucosal damage.

Breast milk may stimulate offspring immune system development. The thymus is larger in infants either breastfed earlier or later in infancy compared with those who received formula.Reference Hasselbalch, Jeppesen, Engelmann, Michaelsen and Nielsen 91 , Reference Hasselbalch, Engelmann, Ersboll, Jeppesen and Fleischer-Michaelsen 92 Thymic enlargement in breastfed infants is associated with increased number of circulating CD8+ (cytotoxic) T-lymphocytes.Reference Jeppesen, Hasselbalch, Lisse, Ersboll and Engelmann 93 Breastfeeding appears to strengthen a child’s immunological response against certain vaccinations.Reference Hahn-Zoric, Fulconis and Minoli 94 Breastfed children demonstrate protection for several years afterwards against various pathogens, including Haemophilus influenza type B, respiratory tract infections, otitis media and diarrhea.Reference Silfverdal, Bodin and Hugosson 95 – Reference Saarinen 98 Select reports indicate that breastfeeding might provide some protection against allergic diseases, such as asthmaReference van Odijk, Kull and Borres 99 – Reference Lodge, Tan and Lau 102 but to a lesser extent for eczema and allergic rhinitis.Reference Lodge, Tan and Lau 102 However, other cohort studies suggest that breastfeeding does not reduce the incidence of later offspring allergic diseases.Reference Jelding-Dannemand, Malby Schoos and Bisgaard 103 , Reference Morales-Romero, Bedolla-Barajas, Lopez-Vargas and Romero-Velarde 104 Additional studies report breastfeeding interacts with other factors, such as genetic background and maternal probiotic supplementation, to reduce atopic diseases.Reference Rautava, Kainonen, Salminen and Isolauri 105 , Reference Lee, Kang, Kwon, Park and Hong 106 Any beneficial effects of breastfeeding on offspring immune responses may be due to stimulation of helper T (Th) sub-type-1 development, which produce more Il2 and IFN-γ than Th2 cells, cells who instead are characterized by greater production of IL4, Il10 and Il13.Reference Field, Clandinin and Van Aerde 107

Offspring cancer

Several cohort and meta-analysis studies provide support for the notion that breastfeeding reduces the incidence of leukemia, especially acute lymphoblastic leukemia, Hodgkin’s Lymphoma, and acute myeloblastic leukemia.Reference Kwan, Buffler, Abrams and Kiley 108 – Reference Bener, Hoffmann, Afify, Rasul and Tewfik 112 The potential beneficial effects of breastfeeding on preventing offspring cancer are less clear with one study indicating this practice diminishes the incidence of brain, germ cell, bone, retinoblastoma and hepatic tumors,Reference Kucukcongar, Oguz and Pinarli 109 whereas, two other studies found no evidence that breastfeeding decreases the incidence of childhood central nervous system tumors.Reference Greenop, Bailey and Miller 110 , Reference Harding, Birch, Hepworth and McKinney 113

Offspring neurobehavioral development

A cohort study with 1267 Chinese children found that those who were breastfed and whose mothers actively engaged with them demonstrate a reduced risk for later internalizing problems.Reference Liu, Leung and Yang 114 A Copenhagen perinatal cohort suggests that breastfeeding may provide some protective affects against later development of offspring schizophrenia.Reference Sorensen, Mortensen, Reinisch and Mednick 115 Conduct problems are reduced in middle aged children who were breastfed.Reference Shelton, Collishaw, Rice, Harold and Thapar 116

While there is a great deal of interest as to whether breastfeeding can reduce the risk or severity for complex neurobehavioral disorders, such as autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD), robust and unequivocal data are lacking. One case–control study with data obtained from the Autism Internet Research Survey representing 861 children with ASD and 123 control children reported those who were not breastfed or provided infant formula lacking docosohexaenoic acid and arachidonic acid for more than 6 months have a greater odds of developing autism.Reference Schultz, Klonoff-Cohen and Wingard 117 It has been postulated that certain autistic conditions might be related to newborn IGF production deficiencies and the presence of this growth factor in breast milk may compensate for this shortage.Reference Steinman and Mankuta 118 , Reference Steinman and Mankuta 119 A retrospective analysis of children 6–12 years of age who were diagnosed with ADHD relative to those without this disorder indicated breastfeeding may protect male and female offspring from developing this disorder.Reference Mimouni-Bloch, Kachevanskaya and Mimouni 120 Although such studies provide hints that breastfeeding may combat against developing complex neurological diseases, the findings may also be due to other confounding factors. These include genetics, environmental background, nutritional, overall health, socioeconomic, nutritional and metabolic status of both parents to list a few examples. Thus, larger cohort studies spanning genetically related and unrelated children of varying ages and backgrounds are needed before any firm conclusions can be drawn.

Several studies have examined whether breastfeeding improves later offspring cognitive abilities and IQ status, as measured by several indices. The general consensus is that breastfeeding can improve both of these parameters to a certain extentReference Schack-Nielsen and Michaelsen 74 , Reference Victora, Bahl and Barros 75 , although there are conflicting dataReference Tozzi, Bisiacchi and Tarantino 121 – Reference Der, Batty and Deary 123 . Those reporting a positive association also suggest that the effects of breastfeeding on IQ score become more pronounced with increased breastfeeding duration and are enhanced in preterm infants or those small for gestational age.Reference Schack-Nielsen and Michaelsen 74 , Reference Victora, Bahl and Barros 75 , Reference Slykerman, Thompson and Becroft 124 Genetic variation in the FADS2 gene, which regulates fatty acid pathways, may modulate breastfeeding effects on IQ status.Reference Caspi, Williams and Kim-Cohen 125 While it is beyond the scope of the current article to discuss all studies to date, representative individual and meta-analyses reports will be considered.

A meta-analyses study of 11 individual reports with children ranging from 6 months to 16 years of age concluded that breastfeeding positively correlated with an increase in IQ by 3.2 points, even after controlling for covariant variables, namely maternal intelligence.Reference Anderson, Johnstone and Remley 126 Another meta-analyses representing 17 individual studies also found an increase of 3.4 IQ points in breastfed children and adolescents.Reference Horta, Loret de Mola and Victora 127 A prospective longitudinal birth cohort with a sample of 973 men and 2280 women who were born in Copenhagen, Denmark between October 1959 and December 1961 determined that breastfeeding up to 9 months of age is linked with higher adult intelligence.Reference Mortensen, Michaelsen, Sanders and Reinisch 128

Intelligence as measured by the Peabody Vocabulary Test in sibling pairs (n=2734) from the National Longitudinal Study of Adolescent Health showed breastfed infants scored 1.7 and 2.4 higher intelligence points within and across families, respectively, with each month of breastfeeding raising IQ by 0.2 points per month.Reference Evenhouse and Reilly 129 Similar positive benefits for each month of being breastfed and later IQ scores were demonstrated in two consecutive generations of British children enrolled in the National Child Development Study.Reference Kanazawa 130 A Krakow prospective birth cohort study revealed that breastfeeding alone positively associates with an increase in IQ of toddlers by 1 year of age and this effect persists through the preschool period.Reference Jedrychowski, Perera and Jankowski 131 A causal relationship of breastfeeding duration and receptive language and verbal and nonverbal intelligence in school age children (3 and 7 years of age) was established in a U.S. cohort representing 1312 mothers and children.Reference Belfort, Rifas-Shiman and Kleinman 132 Eight-year-old children who were breastfed for 6 months or more performed better in a general intellectual assessment test.Reference Fonseca, Albernaz, Kaufmann, Neves and Figueiredo 133 Children (6.5-year old, n=13,889) from a Belarussian study who were breastfed achieve elevated scores in verbal, performance, and full scale IQ tests, and are ranked higher in teacher’s evaluations for academic performance in reading, writing and mathematics.Reference Kramer, Aboud and Mironova 134

Causal effects of breastfeeding on IQ but not blood pressure and BMI are suggested based on two cohort children studies (British Avon Longitudinal Study of Parents and Children, ALSPAC and Brazilian Pelotas 1993 cohort) representing ~6000 male and female individuals and a follow-up meta-analysis results from five low- or middle-income countries (LMIC, n≈10,000).Reference Brion, Lawlor and Matijasevich 135 A separate meta-analyses concluded breastfeeding may increase intelligence, protect against child infections and malocclusion, and reduce the incidence of obesity and diabetes.Reference Victora, Bahl and Barros 75

Ostensibly, the beneficial effects of breastfeeding on neurobehavioral development are multi-faceted. One possibility is that breastfeeding may directly shape brain development. In males, breastfeeding is associated with an increase in IQ and enhancing brain white matter growth, presumably due to an increase in neuronal cell processes or dendritic arborization.Reference Isaacs, Fischl and Quinn 136 Nutrients within the milk may stimulate neural programming. Two primary ones that have received considerable attention are essential and nonessential long-chain (LC) polyunsaturated fatty acids (PUFA) and the n-3 fatty acid, docosahexaenoic acid (DHA).Reference Schack-Nielsen and Michaelsen 74 Supplementation of DHA to lactating mothers is associated with improved psychomotor indices in 30-month-old children, but this treatment did not affect visual acuity or neurocognitive development.Reference Jensen, Voigt and Prager 137 LC-PUFA in colostrum may boost mental development in children who are breastfed for a prolonged duration.Reference Guxens, Mendez and Molto-Puigmarti 138 Maternal hormones within the milk may also affect later offspring neurobehavioral functions. For instance, greater amount of cortisol in human milk appears to impact infant temperament, as evidenced by a positive association with negative affectivity or emotions in girls.Reference Grey, Davis, Sandman and Glynn 139

Conclusions

Parental factors resulting in disease outcomes in offspring have received considerable attention. Howevever, less so are the steps parents can take to promote the lifelong health of male and female offspring. The current data suggest that parental exercise, probiotic supplementation and breastfeeding may abate the risk of various disorders and even foster beneficial effects. However, there are still important unanswered questions and concerns to be addressed.

One of the primary questions is whether beneficial parental habits can mitigate negative perinatal influences. For instance, breastfeeding ameliorates the deleterious metabolic effects in children born to mothers who endured pre-gestational diabetes or excessive weight gain.Reference Feig, Lipscombe, Tomlinson and Blumer 81 , Reference Zhu, Hernandez and Dong 82

In rodents, maternal exercise abolishes the deleterious effects of developmental exposure to a high fat or protein restricted diet.Reference Raipuria, Bahari and Morris 35 , Reference Wasinski, Bacurau and Estrela 39 , Reference Sheldon, Nicole Blaize and Fletcher 41 – Reference Amorim, dos Santos and Hirabara 43 Additional studies are needed though to examine whether breastfeeding, exercise, and probiotic administration can combat other negative extrinsic influences, such as stress and environmental chemicals. It is becoming increasingly apparent that gut microbial populations and their by-products can affect various systems ranging from cardiometabolism to the central nervous system. Thus, early colonization with beneficial microbes might protect neonates against harmful stimuli. Yet, there are currently no studies examining concurrent exposure to maternal or paternal obesity, exposure to environmental chemicals, stress or other harmful factors and probiotic supplementation.

Moreover, it would be of interest to determine the collective DOHaD effects of all three presumably beneficial factors, especially in sub-optimal perinatal conditions. Exercise and breastfeeding may alter the gut microbiome of parents and their offspring. As indicated above, breast milk induces long-term offspring gut microbiome changes that can have dramatic health consequences.Reference Rogier, Frantz and Bruno 89 , Reference Rogier, Frantz and Bruno 90 In adult rodents, exercise changes the gut microbial populations.Reference Campbell, Wisniewski and Noji 140 – Reference Welly, Liu and Zidon 143 In turn, the composition of the gut microbiota may influence exercise performance of mice through anti-oxidant enzyme production.Reference Hsu, Chiu and Li 144 In mice, exercise attenuates gut dysbiosis due to exposure to polychlorinated biphenyls.Reference Choi, Eum and Rampersaud 145 It is likely that similar and possibly even more complex interactions among the gut microbiome, parental exercise and breastfeeding occur in developing neonates.

There are several published studies exploring the effects of maternal exercise and probiotic supplementation on offspring DOHaD outcomes. However, reports examining these effects on the father and their progeny are sparse. In the case of paternal exercise, the two current studies yield conflicting data with one reporting positive effects on cognitive functionReference Yin, Wang and Sun 61 but another suggesting this paternal activity results in offspring metabolic disruptions.Reference Murashov, Pak and Koury 62 Clearly, additional studies are needed to sort out the potential offspring DOHaD outcomes due to paternal exercise and whether there can be transgenerational transmission due to epigenetic changes in the spermatozoa.Reference Murashov, Pak and Koury 62 While fathers cannot provide direct nourishment to the young after birth, additional attention should be paid to whether a healthy diet of the father, and the mother, before conception can lead to long-term beneficial offspring consequences. It is increasingly becoming apparent that sub-optimal paternal diets, those high in fat or protein restricted, can result in negative offspring sequelae,Reference Rando 14 – Reference Bromfield, Schjenken and Chin 21 , Reference Faure, Dupont, Chavatte-Palmer, Gautier and Levy 146 – Reference Fullston, Palmer and Owens 149 but the impacts of a healthy diet have been largely ignored. In conclusion, much work remains on identifying various steps that both parents can adapt to ensure the lifelong health of their offspring and potentially even triumph over negative influences that the conceptus or neonate may encounter. The current work though offers hope that indeed good habits on behalf of parents can place their children on the path to a healthy lifespan.

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Figure 0

Table 1 Animal model studies showing beneficial effects of maternal or paternal changes on offspring DOHaD outcomes

Figure 1

Table 2 Human epidemiological studies or meta-analyses showing beneficial effects of maternal changes on offspring DOHaD outcomes