Essay: The effect of maternal uterine environment on in utero programming

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  • The effect of maternal uterine environment on in utero programming
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This section provides an overview of the effects of maternal environment on in utero programming. In utero development is influenced by native and environmental substances found in the maternal uterine environment and adverse conditions could lead to NCDs later in life. These harmful stimuli can be life style choices such as diet, smoking, drugs and exercise or maternal diseases such as obesity, depression or gestational diabetes mellitus. For example, gestational diabetes mellitus is characterised by a hyperglycemic intrauterine environment that raises the risk of developing diabetes and obesity in adulthood. This seems to be the result of leptin hypermethylation as well as adiponectin and imprinted MEST gene hypomethylation. (Ruchat et al., 2013). This section focuses on maternal choices that can adversely influence in utero programing leading to NCDs development; these include diet, smoking and environmental chemicals.
3.1. Diet
The diet of the mother is essential for normal physiological foetal organ development; inadequate intake or balance of macronutrients affects in utero programming and growth of the foetus. In fact, low birth weight due to foetal growth restriction and high birth weight due to increased foetal growth are linked to a wide range of NCDs (Table 1) (Boo & Harding, 2006). In addition, the composition of the maternal diet can also interfere with the development of the embryo. For instance, consumption of alcohol during preimplantation significantly decreases the methylation of the Igf2/H19 imprinting control region leading to placental growth restriction (Sandovici et al., 2012). Moreover, diets low in folate increase the risk of NCDs because of the important role of folate in DNA methylation and nucleotide synthesis. Administration of folate to agouti female mice prevents the expression of the agouti gene, which is downregulated via DNA methylation. Its expression results in yellow colour, obese, diabetic mice with high risk of tumours (Li et al., 2014).
Table 1. Disease related to foetal growth: Examples of NCDs associated to low or high birth weight (Modified from Boo & Harding, 2006).
Low birth weight High birth weight
Hypertension Polycystic ovary disease
Coronary artery disease Prostate cancer
Non-insulin dependent diabetes Breast cancer
Chronic lung disease Testicular cancer
Schizophrenia Childhood leukaemia
Undernutrition is the most studied nutritional stimuli and is related to an increased risk of hypertension type 2 diabetes, obesity, immune and coronary heart diseases in the offspring. This association has been strongly demonstrated through a series of epidemiological studies summarised in Barker, 1998 and Ojha et al., 2013 (Barker, 1998; Ojha et al., 2013). In fact, when the nutritional demand of the foetus is higher than the placental supply, the embryo initially starts catabolism, consuming its own body reserves. If the nutritional restriction is prolonged, the embryo undergoes several adaptations to facilitate survival. First, metabolic changes cause a decrease of metabolic rate and substrate usage slowing foetal growth. Secondly, the blood flow of the embryo is redistributed by organ-specific vasodilatation to protect the most important organs like the brain. Finally, endocrine changes result in modification of foetal hormones secretion and interactions within the foetus, placenta and mother (Barker, 1998; Yoshimura, et al., 1998). The placenta is also modified to ease survival (see below). The exact mechanism by which these adaptations increase the risk of NCDs later in life remains to be elucidated. Nevertheless, altered organ growth and maturation seems to affect the physiology of several tissues leading to cardiovascular diseases (Figure 1) (Boo & Harding, 2006).
Figure 1. General schema of undernutrition induced in utero programming: foetal undernutrition prevents proper organ growth and maturation that negatively affect the physiology and structure of biological systems such as the kidney or the heart; they present reduced number of nephrons and myocytes, respectively. These adaptations increase offspring risk of developing hyperlipidaemia, diabetes, hypertension and stroke that are common factors of cardiovascular diseases (Modified from Boo & Harding, 2006).
Maternal undernutrition produces multiple alterations in the embryo increasing offspring risk of NCDs later in life. Slow foetal growth and blood redistribution in late gestation causes disruption of kidney anatomy leading to hypertension (see above) (Barker, 1998). In addition, the thrifty phenotype hypothesis proposed by Hales and Barker stipulates that the embryo reduces insulin secretion and increases insulin resistance during undernutrition to conserve more glucose and direct the majority of it to the brain and heart instead to insulin-dependent tissues such as muscle (Boo & Harding, 2006). In concordance, nutritional deficiency is associated with an increase of insulin receptors but a decrease of the catalytic subunits of certain downstream elements in the skeletal muscle. These insulin-downstream elements are protein kinase-B (Akt/PKB) and phosphatidylinositol 3-kinase (PI3K) (Thorn et al., 2009). Later in life, the abundance of nutrients and insulin intolerance leads to diabetes. Furthermore, undernutrition increases DNA methylation of the IGF2/H19 imprinted region in the liver of rat offspring promoting expression of IGF2 that stimulates growth; it also decreases offspring sensitivity to leptin, the satiety hormone. These alterations lead to obesity in later life (Huang et al., 2012; Sarr et al., 2012).
Overnutrition of the embryo is currently gaining importance due to the strong association with offspring developing obesity, a noncommunicable disease whose prevalence has skyrocketed in recent years. In fact, in utero overnutrition seems to increase the risk of obesity, diabetes, hypertension, cardiovascular diseases and early adult death. For instance, the children of obese women that lost weight presented different risk of being overweight in adulthood. Children born when the mothers were normal weight had half the risk of becoming obese than their older siblings born when the mothers were obese (Koletzko et al., 2012). Moreover, pregnant rats on a high-fat diet had offspring with hypertension and defective glucose homeostasis (Boo & Harding, 2006). The developmental overnutrition hypothesis suggests that the effects of foetal overnutrition are based on different adaptations affecting control of the appetite, development of adipocytes, metabolism and endocrine axis (Figure 2); recent studies demonstrate an altered control of energy balance by the hypothalamus (Ojha et al., 2013).
Figure 2. General schema of overnutrition induced in utero programming: foetal overnutrition is associated with an excess of nutrients that altered physiology and structure of the hypothalamus, adipose tissue, liver and pancreas in the offspring. These adaptations increase the risk of obesity, metabolic syndrome and early adult death in later life (Modified from Ojha et al., 2013).
The nutritional status of the embryo also depends considerably on the placenta, a transient organ in the interface between the mother and the embryo that is responsible for nutrient transport and contribute to hormone production. This organ adapts its activity to demand signals from both, the mother and the foetus. The foetus demands an increase in the transfer of nutrients to facilitate embryo development while the mother prevents excess transfer of maternal resources (Sandovici et al., 2012; Jansson & Powell, 2013). Abnormal intrauterine environment induces placental adaptation to optimize embryo development and ease survival. These adaptations can affect the placental size, structure and physiology. For example, reduction of nutrient availability might be associated with an increase in placental volume to compensate and increase nutrient transport (Sandovici et al., 2012). Moreover, undernutrition decreases placental activity of 11??HSD2, a dehydrogenase that catalyses the inactivation of cortisol (Wyrwoll, et al., 2009). The consequent excessive cortisol exposure in utero reduces amino acid transport by the placenta and increases the risk of hypertension as well as type 2 diabetes in offspring. On the contrary, overnutrition is associated with increased placental transport of amino acids, glucose and lipids (Sandovici et al., 2012; Jansson & Powell, 2013).
3.2. Smoking
Cigarette smoke is a very common stimulus in the environment that can affect in utero programming. Around 13% of American pregnant women continue smoking during pregnancy and large numbers are also passively exposed to cigarette smoke. Moreover, some toxic constituents of this smoke can cross the placenta. In fact, smoking is associated with an increased risk of developing cancer, neurological conditions, atherosclerosis, low birth weight as well as respiratory and cardiovascular diseases (Ng et al., 2009; Maccani & Knopik, 2012).
Evidence shows that rats exposed to cigarette smoke in utero presented defective vascular function with increased sensitivity to vasoconstriction and reduced relaxation (Ng et al., 2009). Furthermore, cigarette smoke exposure of female mice resulted in sex-dependent increase in birthweight of offspring in which females exhibit greater susceptibility to weight gain. Similarly, cigarette smoke exposure was also associated with sex-dependent dyslimidemic profile in which females had higher concentration of LDL and HDL. The proatherogenic phenotype, due to high LDL concentration, can lead to increase LDL oxidation in blood vessel walls and development of atherosclerosis later in life (Ng et al., 2009).
The underlying mechanisms of these adaptations and their involvement in NCDs development need to be elucidated. Nevertheless, evidence suggests an important role of epigenetic modifications. Adults exposed to cigarette smoke in utero present hypomethylation of AluYb8 repeat and hypermethylation of AXL gene (Suter et al., 2013). Moreover, cigarette smoke downregulates expression of microRNAs in placenta; nicotine and benzene strongly repress miR-146a (Maccani & Knopik, 2012).
3.3. Environmental chemicals
Everyday people are exposed to environmental chemicals from common sources such as cosmetic products, body creams and pharmaceutical treatments. These chemicals might influence in utero programming threating proper organ differentiation and physiology, which increase the risk of NCDs in the offspring. For instance, evidence suggests that bisphenol A (BPA) and some analgesics like paracetamol, aspirin and indomethacin augment offspring risk of certain NCDs such as infertility.
BPA is an endocrine disrupting chemical found in plastic used to make daily goods such as water bottles, dental fillings and inner lining of food cans. In addition, BPA have been found in several elements such as air, water and dust as well as in some biological samples such as hair, breast milk and placenta (Liao & Kannan, 2014). Evidence suggests that BPA might be associated with subfertility in adulthood (Veiga-Lopez, et al., 2014). Recent studies have shown that BPA exposure in utero, at doses relevant to humans, causes shortening of the time between estradiol rise and LH surge as well as modification of ovarian follicular dynamics; it results in variable occurrence of follicular waves and alteration of follicular counts. Shortening of the estradiol-LH surge interval suggests that the positive feedback of estradiol to generate the LH surge and promote ovulation is altered. This seems to be caused by an increase sensitivity of the hypothalamic-pituitary axis to oestrogen and an earlier upregulation of gonadotropin-releasing hormone receptor (GnRHR) in the pituitary. BPA increases expression of oestrogen receptor 1 (ER1) and reduces expression of oestrogen receptor 2 (ER2) in the hypothalamus which promotes and inhibits LH surge, respectively. Furthermore, the low follicular count might be related to BPA-decrease of Cyp19a1 mRNA expression because this aromatase is essential for follicular growth (Veiga-Lopez et al., 2014).
In addition to BPA, certain analgesics also cause adverse in utero programming and increase offspring risk of NCDs. In fact, consumption of paracetamol, aspirin and indomethacin during pregnancy is associated with cryptorchidism (undescended testes), the main risk factor of testis cancer and male infertility later in life. Recent studies suggest that these analgesics inhibit production of insulin-like factor 3 (INSL3) that is involved in the first step of testis descendent. They present different windows of sensitivity in which they can interfere with in utero development and predispose to infertility and testicular cancer in adulthood (Mazaud-Guittot et al., 2013).
4. Noncommunicable diseases: outcomes of defective in utero programming.
In this section of the essay the strong relationship between NCDs and defective in utero programming is illustrated. NCDs are a major problem of the current society that seems to stem mainly from defective in utero programming. According to the World Health Organization (WHO), they are the current leading cause of death around the world, with the exception of Africa. Approximately 36 million people die every year due to NCDs and around 9 million of these are premature deaths. Furthermore, NCDs pose a huge economic threat because they require expensive treatment and reduce the working population, either through incapacitation or premature death. For instance, in 2005 India and Brazil lost $9 and $3 billion, respectively, due to diabetes, heart conditions and strokes (Roura & Arulkumaran, 2015). As a consequence, identification of the causes and prevention of NCDs are strongly required. An increasing amount of evidence demonstrates the defective in utero programming origin of a broad range of NCDs (Table 2).
Table 2. Examples of NCDs caused by defective in utero programming.
NCDs Stimuli Proposed mechanisms References
Cardiovascular diseases ‘ Overnutrition
‘ Undernutrition
‘ Cigarette smoke
‘ Altitude
‘ Preeclampsia
‘ Hypercholesterolemic diet
‘ Alteration of oxidation-sensitive signalling pathways in the arterial wall.
‘ Enhance fatty streak formation
‘ Imprinting and epigenetic alterations.
‘ Downregulation of placental glucose transporter (Palinski & Napoli, 2002; Napoli et al., 2011; Davis et al., 2012; Sandovici et al., 2012)
Asthma ‘ Non-specific environmental factor ‘ Defective epigenetic gene silencing (Bousquet et al., 2004)
Breast Cancer ‘ High oestrogen levels
‘ High birth weight
‘ Low progesterone levels.
‘ High-fat diet
‘ Alcohol ‘ Increased IGF-1 expression.
‘ Reduced IGFBP-3 expression. (Baik et al., 2004; Grotmol et al., 2006)
Testicular Cancer ‘ High oestrogen levels.
‘ High birth weight.
‘ Low birth weight.
‘ High anti-androgens levels ‘ Disturbed in utero development of gonads (Grotmol et al., 2006)
Vaginal adenocarcinoma ‘ Diethylstilbestrol (DES) ‘ Endocrine abnormalities (Palmer et al., 2002)
Mental health diseases ‘ Stress ‘ Epigenetic alterations
‘ Decreased serotonin secretion
‘ Defective cortex maturation
‘ Altered expression of neuroreceptors (Markham et al., 2010; Booij et al., 2012; Holloway et al., 2013; Babenko et al., 2015)
This section focuses on the potential role of in utero programming in the development of mental health diseases; medical conditions affecting almost half of the population in the World (Babenko et al., 2015).
4.1. Mental health diseases
Stressful experiences during pregnancy are strongly associated with an increased risk of mental NCDs such as Alzheimer, Parkinson, schizophrenia, autism, anxiety and depression. In fact, epidemiological studies showed that maternal stress due to unwanted pregnancies, bereavement and natural disasters is related to higher risk of developing schizophrenia later in life; children of pregnant women during the Arab-Israeli war exhibited increased risk of this disease (Babenko et al., 2015).
Stress is a biological response against adverse events that promotes secretion of adrenocorticotrophic hormone (ACTH) and glucocorticoids (CORT). CORT are beneficial in the short term but long time elevation might be deleterious for the nervous system, mainly during in utero development of the brain (Babenko et al., 2015). In fact, a study showed that human foetal brain tissue exposed to CORT in vitro exhibited altered expression of 1648 mRNAs (Salaria et al., 2006). Moreover, stress decreases the production of serotonin in cortex and hippocampus. Since this neurotransmitter plays a role in the regulation of emotions, these alterations increase the risk of psychiatric disorders later in life (Booij et al., 2012). Furthermore, evidence depicts that epigenetic modifications of in utero stress-exposed offspring are similar to mRNA and DNA methylation signatures of specific mental health diseases (Zucchi et al., 2013).
Defective in utero programming caused by stress is likely to predispose the foetus to schizophrenia. Stress during late gestation causes sex-specific defects in the cortex maturation disturbing male dendrites maturation as well as altering expression of serotonin 2A and glutamate 2 receptors. These alterations are associated with social problems and schizophrenia later life (Markham et al., 2010; Holloway et al., 2013). Similarly, anxiety and depression are associated to stress-caused placental defects. Stress inhibits placental activity of 11??HSD2 and NR3C1 through hypermethylation of these genes, which are involved in regulation of foetal cortisol exposure; these inhibitions increase cortisol levels in the embryo. The excess of cortisol negatively affects the hypothalamic-pituitary-adrenal axis rising ACTH and cortisol levels in the offspring and reducing quality of movement; defective motor control is associated with learning difficulties later in life (Conradt et al., 2013).
5. In utero programming: a new approach of preventive medicine.
This section of the essay provides an overview of the potential role of in utero programming in prevention of NCDs in later life. Prevention of NCDs is a main global health issue and the defective in utero programing origin of these diseases suggests that new approaches based on this programming could be developed to protect offspring against these diseases. Moreover, recent evidence suggests an epigenetic transgenerational effect, in other words, in utero programing-induced epigenetic modifications can affect several generations and predisposition to NCDs may be transmitted (Boo & Harding, 2006; Napoli et al., 2011). Therefore, approaches based on in utero programing can induce transgenerational protection against these diseases. The International Federation of Gynaecology and Obstetrics (FIGO) recognises the importance of supporting pregnant women to reduce the incidence of NCDs and, within other agencies, plans to improve prenatal care programs assuring early detection and treatment of maternal diseases as well as promoting proper education of mothers about the risks of environmental and nutritional exposures (Roura & Arulkumaran , 2015). Nevertheless, implementation of health promotion programmes or other approaches based on in utero programming does not guarantee that pregnant women will follow the recommendations or treatments. For instance, it is well known that smoking is deleterious for the embryo and many women continue smoking during pregnancy. This section focuses on two approaches based on positive in utero programming termed in utero programming treatment & immunization and epigenetic diets. Additionally, it also explores a third approach based on postnatal matching to the predictive adaptive response.
5.1. In utero programming treatment & immunization
Understanding the underlying mechanisms of in utero programming leading to NCDs predisposition in offspring would allow the development of specific treatments to prevent adaptations to occur. For instance, it is well known that maternal hypercholesterolemia predispose atherosclerosis in later life due to increase lipid peroxidation and foetal fatty streak generation; maternal treatment with cholesterol lowering agents such as cholestyramine as well as with antioxidants reduces offspring risk of developing this disease (Palinski & Napoli, 2002).
The knowledge of the underlying mechanisms would also allow the development of maternal immunization therapies to protect offspring. In fact, immunization of hypercholesterolemic mice with OxLDL induces antibody-mediated immune response against a broad range of oxidation-specific epitopes, which seems to decrease risk to atherosclerosis, insulin resistance and type 2 diabetes. Therefore, reducing offspring risk of cardiovascular disease later in life (Eberle et al., 2012).
5.2. Epigenetic diets
The influence of nutrition components on in utero programming has given rise to the concept of epigenetic diet. This diet contains bioactive compounds that affect epigenetics processes reducing the risk of developing certain NCDs such as cancer or cardiovascular diseases. Identification of these biological products (Table 3) and consumption of them at the developmental stages when in utero programming is more susceptible to their action may become an efficient preventive measure against NCDs (Li et al., 2014).
Illustrations of bioactive compounds are genistein and SFN. Genistein is a phytoestrogen found in soybean products that seems to modify the hypermethylated phenotype of the agouti mice decreasing obesity as well as protecting against mammary gland cancer later in lifer. Furthermore, SFN, an isothiocyanate found in certain vegetables, reduces the risk of some cancers; maternal SFN enriched diet prevents offspring of spontaneous mammary gland cancer mouse model to develop this disease (Li et al., 2014).
Table 3. Protective effects of dietary components: Examples of bioactive compounds found in different foods that prevent development of certain NCDs (Modified from Li et al., 2014).
Bioactive compounds Food sources Effects
Genistein Soybean products Protects against obesity and breast cancer
Sulforaphane Cruciferous vegetables like cabbage and broccoli Protects against several cancers
EGCG (Polyphenol) Green tea Protects against chronic diseases and cancer
Indole-3-carbinol Cruciferous vegetables Protects against lung cancer
5.3. Postnatal matching to predictive adaptive response
The predictive adaptive response hypothesis stipulates that the foetus adapts to changes in the intrauterine environment to facilitate survival. These changes may be reversible but if the stimuli persist they will become irreversible to prepare the embryo for the immediate extrauterine environment. However, disparities in the later environment, respect what was expected, may lead to NCDs later in life. Therefore, assuring an extrauterine environment similar to the predicted one may correct the adaptations via postnatal programming and reduce predisposition to NCDs. For example, one study demonstrated that offspring of high-fat fed rats exhibited hypertension and defective endothelial function. In addition, postnatal feeding of the offspring with high-fat diet prevented altered endothelial function although not hypertension (Boo & Harding, 2006).
6. Conclusion
In summary, in utero programming is undoubtedly involved in the predisposition to noncommunicable diseases in the offspring. This influence is based on the great plasticity of embryonic development in which adverse stimuli can lead to anatomical disruptions and epigenetic modification. These alterations have subtle effects on tissue physiology leading to an increased risk of the offspring developing NCDs later in life.
The role of in utero programing in offspring predisposition to NCDs has been elucidated in three examples that discuss the effects of maternal stimuli on offspring health. The first one depicts the influence of maternal diet on embryonic development indicating the epigenetic, structural and placental adaptations caused by undernutrition and overnutrition increasing the risk of cardiovascular diseases. The second example shows the negative effects of smoking that promotes NCDs such as atherosclerosis in adulthood. Finally, the third example indicates the effects of environmental chemicals on NCDs predisposition such as infertility.
This essay also illustrates the huge amount of NCDs resulting from defective in utero programing focusing on the development of mental health diseases. In addition, the potential role of in utero programming in prevention of NCDs in later life and in future generations is also discussed. In fact, FIGO plans to improve maternal education to prevent pregnant women from getting in contact with risk stimuli for NCDs. Furthermore, in utero programming treatment & immunization and epigenetic diets, approaches based on positive in utero programming, could reduce predisposition to NCDs and decrease their incidence in future generations of families with NCDs history. Moreover, postnatal matching to the predictive adaptive response could correct adverse in utero programing and reduce predisposition to NCDs.
Although in utero programming plays an important role in disease predisposition in offspring, many unknowns remain to be answered. What other stimuli negatively affect in utero programming? Is in utero programming more or equally important than postnatal programing in the development of NCDs? And can prenatal health programmes, based on positive in utero programming, reduce transgenerational effects and protect offspring against NCDs? In consequence, future perspectives should address the study of other nutritional factors, recreational habits and daily chemicals that could negatively affect in utero programming as well as develop the concept of positive in utero programming as a tool of preventive medicine, an essential approach in the reduction of NCDs or even their eradication.

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