Prenatal nutrition and prenatal environmental exposure affect organogenesis of t
ID: 186173 • Letter: P
Question
Prenatal nutrition and prenatal environmental exposure affect organogenesis of the human embryo and fetus. Provide support for this hypothesis using citations from the scientific literature (search the pubmed.gov Website) to demonstrate how prenatal nutrition affects organogenesis in the embryo and fetus. Specifically, discuss how maternal diet, vitamin intake, prenatal supplementation, prenatal exposure to dietary heavy metals promote or other toxins can regulate organogenesis, especially during weeks 4-8 of life. include citations plzExplanation / Answer
The prenatal period is a sensitive time during which intrauterine exposures can modulate the course of development and confer an enduring effect on the offspring. Epidemiological and animal studies have demonstrated that prenatal programming of physiological systems can alter the growth and function of organ systems and pathology into adulthood (Szekeres-Bartho, 2002; Mold and McCune, 2012). For example, early immune system programming would give rise to changes in the fetal immune system that persists over the life course. In addition, some evidence based on animal, epidemiological and genetic studies suggests that immune dysregulation in the developing brain may play a role in neurodevelopmental disorders such as autism spectrum disorder and schizophrenia (Brown et al., 2000a, 2004; Susser et al., 2000; Meyer et al., 2009; Patterson, 2009, 2012; Meyer and Feldon, 2010; Bilbo and Schwarz, 2012; Aberg et al., 2013).
During pregnancy, the maternal and fetal immune systems communicate in a bi-directional manner. The maternal immune system develops an active immunologic tolerance against fetal-placenta antigens (recognition and activation). Following recognition, the maternal immune system reacts with a wide range of protective immunoregulatory mechanisms, which are critical for the maintenance of a normal pregnancy, the development of the fetal immune system, and maintaining maternal immunocompetence (Szekeres-Bartho, 2002; Mold and McCune, 2012; Erlebacher, 2013).
While well-controlled maternal immune responses play a positive physiological role in fetal immune and nervous system development, an inappropriate maternal immune activation (e.g., increased levels of pro-inflammatory cytokines) may contribute to an increased risk in the offspring of neurodevelopmental disorders, autoimmune diseases and allergies later in life (Brown et al., 2004; Bresnahan et al., 2005; Ellman and Susser, 2009; Bilbo and Schwarz, 2012). The timing of immune dysregulation, with respect to gestational age and neurologic development of the fetus, may be significant, as distinct immune and neurodevelopmental programs are affected differently depending on fetal stage. This creates a sensitive window of vulnerability (Dietert and Dietert, 2008).
The fetal immune system is particularly vulnerable to disruptions caused by environmental factors that have an impact on the maternal immune system, such as malnutrition, toxins and stress. We will discuss the effects of maternal and infant nutrition and maternal stress and anxiety on perinatal programming of immune function, and how this might influence neurodevelopment (Palmer, 2011; PrabhuDas et al., 2011; O'Connor et al., 2013b).
Based on these findings, we will discuss the implications for preventions of neurodevelopmental disorders focused on nutrition, as diet is among the more easily manipulated, safe, and promising avenues for intervention. We will highlight examples of three micronutrients—folate, iodine, and vitamin D—and discuss their proven and potential preventive effects on neurodevelopmental disorders. Although certain micronutrient supplements have shown to both reduce the risk of neurodevelopmental disorders and enhance fetal immune development, we do not know whether the impact on immune development contributes to the preventive effect on neurodevelopmental disorders. Future studies are needed to elucidate this relationship, which could contribute to better understanding of the mechanisms of prevention and in turn perhaps improvements in these interventions.
The impact of maternal and infant nutritional status on immune system development and neurodevelopment
Maternal and infant nutrition may modulate the immunologic development of the fetus and young infant and permanently alter immunologic and regulatory mechanisms, which may affect the risk for later disease (Palmer, 2011). Adequate nutrition is necessary both for establishing the immune system, through normal organogenesis and development, and for an adequate immune response, through the normal proliferation of immune cells and the synthesis of secretory products and acute-phase proteins. Some nutrients, like antioxidants, are also needed to control or inhibit the immune response. Finally, the immune response in itself may affect nutritional status by decreasing levels of certain nutrients, exemplified by the decrease in iron, pyridoxine and tryptophan associated with inflammation (Lotto et al., 2011; Gaffney-Stomberg and McClung, 2012; von Bubnoff and Bieber, 2012).
Maternal malnutrition
During pregnancy, maternal malnutrition hampers placentation, with resulting changes in placental size, morphology and blood flow (Belkacemi et al., 2010) that thereby reduce the supply of nutrients to the fetus. The subsequently compromised fetal nutrition status has profound effects on organogenesis, growth and fetal programming and has been associated with both short- and long-term effects on development and morbidity (Jansson and Powell, 2007).
Maternal malnutrition interferes with both the quality and quantity of immune factors transferred prenatally through the placenta and postnatally through the mammary gland (Palmer, 2011). Maternal IgG is actively transported through the placenta, appearing in the fetus (Simister, 2003) and remaining intact in the infant up to the age of 3–6 months (Palmer, 2011). The highest levels of maternal IgG in the cord blood is found during the last 4–6 weeks of pregnancy, so premature birth is associated with lower IgG levels in the infant (Malek et al., 1996). Reduced IgG levels have also been observed in small-for-gestational-age infants and in infants born to mothers with a lower than normal weight for height (Okoko, Wesumperuma, and Hart, 2001). In human milk the main antibody is IgA, which constitutes part of the mucosal immune system that controls epithelial colonization of microorganisms and inhibits penetration of harmful substances (Brandtzaeg, 2011).
A window of opportunity
Development of oral tolerance depends on interactions between maternal, infant and environmental factors, including genetics, food and bacterial colonization. Breast milk is essential for development of oral tolerance and contains immunoglobulins, cytokines, growth factors, lysozyme, lactoferrin, and human milk oligosaccharides. Maternal and infant nutrition modulate immune system development by providing food antigens. Food-derived antigens are transferred through the placenta into the amniotic fluid and cause prenatal formation of antigen-specific IgE antibodies (Kondo et al., 1992). After birth, introduction of breast milk, formula and solid food influences immune maturation and response in a complex interaction with gut flora (Calder et al., 2006). There appears to be a window of opportunity for optimal development of oral tolerance between 4 and 6 months of age. Impaired oral tolerance is associated with gut inflammatory disease, food allergies and celiac disease (Verhasselt, 2010). Impaired oral tolerance was exemplified by an experience in Sweden between 1984 and 1996, during which an epidemic of coeliac disease in children <2 years occurred following changing of feeding habits and delaying introduction of gluten from 4 months to 6 months (Ivarsson et al., 2013).
Micronutrients
Maternal deficiency of certain micronutrients is reported to permanently affect the immune system, but much remains unknown about this area. Gestational zinc deficiency has been associated with reduced thymic and spleen size, decreased antibody concentrations and impaired lymphocyte activity (Wellinghausen, 2001). Nutritional factors related to single carbon metabolisms, choline, folate (which is necessary for DNA methylation) and vitamins B2, B6, and B12 are important modulators for epigenetic mechanisms (Dominguez-Salas et al., 2012). Changes in the epigenetic regulation of immune system development have been linked to various pathological conditions, among them allergic risk and asthma development (Martino and Prescott, 2011). Dietary folate is postulated to be necessary for the maintenance of Forkhead box P3 (FOXP3) Tregs in the colon, a subset of inhibitory CD4+ helper T-cells that restrain the immune response to infection, inflammation and autoimmunity. Conversely, mice fed a diet deficient in folic acid have a higher susceptibility to intestinal inflammation (Kinoshita et al., 2012).
Fat-soluble vitamins A and D play important roles in both cell-mediated and humoral immune responses (Wintergerst et al., 2007). Vitamin D is a direct regulator of antimicrobial innate immune responses, can inhibit lymphocyte proliferation (Wang et al., 2004) and promote development of Tregs (Lemire et al., 1984). Vitamin D deficiency in healthy neonates has been linked to an increased risk of respiratory syncytial virus infection during the first year of life. Vitamin A has also been shown to be necessary for the development of de novo Tregs in the gut (Sun et al., 2007). Vitamin A deficiency has been reported to seriously affect hematopoiesis (Oren et al., 2003) and has been associated with a substantial increase in morbidity and mortality, especially due to diarrhea and measles in young infants (Fawzi et al., 1993).
It has also been suggested that maternal intake of vitamin E and polyunsaturated fatty acids during pregnancy may influence development of the immune system and be implicated in childhood asthma and allergy. Published reports, however, show conflicting results, and intervention studies are still lacking (Devereux, 2010).
Environmental contaminants
Food not only provides nutrients but is also the most important source of environmental contaminants, specifically persistent organic pollutants (POPs). This is a group of highly resistant chemicals, including dioxins, furans, polychlorinated biphenyls and organochlorine pesticides, created by industrial activities and found in food, with the highest concentrations in fatty fish (primarily farmed salmon) (Schecter et al., 2010). These highly toxic compounds have been found to cross the placenta and to be excreted in breast milk (Fromme et al., 2010), thereby effectively clearing the amount of POPs in maternal tissue by up to 94% (Thomsen et al., 2010; Whitworth et al., 2012). The rapidly developing infant receiving this breast milk has immature organ systems and is especially vulnerable for toxic effects.
Early life exposure to various xenobiotics, including POPs, is associated with developmental immunotoxicity, which has been linked to neurodevelopmental disorders like autism spectrum disorders (for review see Dietert and Dietert, 2008). Epidemiological and human studies have demonstrated that there is a complex interaction between the immune system, environmental pollutants and neurodevelopment, although the exact mechanisms are still not well understood (Park et al., 2010). However, pre-, peri- and postnatal exposure to POPs is clearly associated with brain damage (Ribas-Fito et al., 2001; Walkowiak et al., 2001).
Dietary Patterns
Evidence from international scientific research has identified various eating patterns that may provide short- and long-term health benefits, including a reduced risk of chronic disease. Analysis of overall food patterns takes into account the complex interactions and cumulative effects of multiple nutrients in the entire diet, therefore offering a more comprehensive and complementary approach to public health.
The “Western” diet is a pattern of eating that is associated with adverse health outcomes. The typical Western diet is one low in fruits, vegetables, whole grains, fish/seafood, and low-fat dairy. It is often called the meat-sweet diet because it is high in refined sugars, refined grains (baked goods, desserts, chips), red meat, and saturated fat. It also typically contains high-sugar drinks, high-fat dairy, and higher intakes of processed meats.
Other traditional eating patterns alternatively can provide health benefits. Their variety demonstrates that people can eat healthfully in a number of ways, which also likely applies to pregnancy.
Several healthful dietary patterns have been inversely associated with the risk of type 2 diabetes mellitus, cardiovascular disease, and total mortality. Examples of healthy dietary patterns include the aMED (alternative Mediterranean diet), DASH (Dietary Approaches to Stop Hypertension), and aHEI (alternative Healthy Eating Index). These healthy dietary patterns share common components, namely, emphasizing a high intake of vegetables and fruits, high-quality carbohydrates including whole grains, protein from beans and smaller amounts from lean meats, healthy fats from nuts and seeds, fish and seafood and liquid oils, high in fiber, low in added sugar, and low intake of red meat and processed meats.
The types of vegetarian diets consumed in the United States vary widely. Vegans do not consume any animal products, whereas lacto-ovo vegetarians consume milk and eggs. Vegan diets can be low in B12, riboflavin, vitamin D, calcium, and long-chain n-3 fats if not properly supplemented. Vegetarian diets can also potentially be low in certain nutrients depending on which food groups might be avoided such as dairy, eggs, and/or fish and seafood, so supplement recommendations should be individualized.
Prepregnancy adherence to dietary patterns is now being investigated, with a few studies showing adherence to healthful dietary patterns being significantly associated with a lower risk of GDM, and a recent study showed that adherence to a Mediterranean diet pattern of eating during pregnancy was associated with lower incidence of GDM and better degree of glucose tolerance even in women without GDM. It has been speculated that these healthy dietary patterns may minimize the susceptibilities a pregnant woman has to -cell dysfunction and insulin resistance.
These data suggest that efforts to encourage dietary patterns similar to the aMED, DASH, or aHEI might yield benefits for women of reproductive age and for pregnant women as well. My Pregnancy Plate is an education tool created using this emerging evidence of healthy eating patterns that can be advocated for in this population.
There is good evidence to support a need for supplementation with folate, iodine, and calcium for all pregnancies. There is good evidence for supplementation with vitamin C in pregnant women who smoke. There is no good current evidence to show value in supplementation for iron and vitamins A, B6, B12, A, E, or D at this time, although there are many suggestive studies for vitamin D. All pregnant women should be encouraged to eat a balanced diet rich in fresh or frozen fruits and vegetables, high-quality carbohydrates including whole grains, and with a good mix of proteins from beans, lean meats, fish, and seafood. Their diet should be low in added sugar, red meat, and processed foods. Information beyond this simple prescription is simply not yet available for pregnant women or their offspring.
Implications for prevention of neurodevelopmental disorder focusing on nutrition
We emphasized in previous sections that optimal development of the fetal immune system depends on adequate maternal nutritional intake and that certain micronutrients play a particularly important role. We also noted that the development of the immune system may modulate the risk for later diseases, including neurodevelopmental disorders. Taken together, these observations raise the question of whether nutritional interventions, and in particular, micronutrient supplements (to mother or baby), could reduce the risk of neurodevelopmental disorders by enhancing early development of the immune system.
Thus far, this question has rarely been addressed directly. We have learned that certain micronutrient supplements both reduce the risk of neurodevelopmental disorders and enhance fetal immune development. But we do not know the relationship between these two effects, or whether the impact of supplements on immune development also contributes to the preventive effect. A useful focus for future research would be to elucidate that relationship, which could lead to a better understanding of the mechanisms of prevention and in turn, perhaps improvements in these interventions. From a global perspective, this is quite a fundamental question for public health, because severe micronutrient deficiencies are widespread in developing countries, and are associated with low birth weight, delayed neurodevelopment, stillbirths, and perinatal and neonatal mortality (Ahmed et al., 2012). The immunological development of the fetus or infant may well play a role in vulnerability to these adverse outcomes (Trehan et al., 2013).
There are several examples of broad nutritional interventions (e.g., encouragement of breastfeeding), as well as many examples of specific micronutrient supplements that fall within this framework (that is, they enhance both immune development and neurodevelopment but the relation between these two effects remains unknown. For illustration, we have selected three micronutrients—folate, iodine, and vitamin D—and discuss their proven and potential preventive effects on neurodevelopmental disorders.
Folate
In an earlier section we described how folate and other B-vitamins can be pivotal for fetal immune development. With respect to neurodevelopmental disorders, periconceptional folic acid supplements have been proven to have a major preventive effect. Worldwide, birth defects affect about 6% of live births (Wallingford et al., 2013). Neural tube defects (NTDs) are one of the most common congenital birth defects and one of the few for which we have knowledge about preventive strategies. Folic acid is a B-vitamin that is important for cell proliferation, (Zeisel, 2009) central nervous system cell repair, (Iskandar et al., 2010) and appropriate epigenetic expression of the genome (Jaenisch and Bird, 2003; Steegers-Theunissen et al., 2009), as well as for immune development (Kjer-Nielsen et al., 2012). Randomized controlled trials have demonstrated that periconceptional folic acid supplements reduce the risk of NTDs (Prevention of neural tube defects: results of the Medical Research Council Vitamin Study, MRC Vitamin Study Research Group, 1991; Czeizel and Dudas, 1992; Berry et al., 1999). All women of childbearing age are recommended to take a folic acid supplement of 400–800 g/d, preferably a month before conceiving. In addition to public health campaigns to increase awareness of taking prenatal folic acid supplements, the US Food and Drug Administration mandated adding folic acid to all enriched cereal grain products in 1998. This fortification policy has been associated with a prevalence decline of 34% for spina bifida and 20% for anencephaly (Honein et al., 2001; Williams et al., 2002; Canfield et al., 2005). Somewhat greater declines are reported for Canada (De Wals et al., 2007) and Chile (Lopez-Camelo et al., 2005). Early detection through prenatal screening is also a likely contributor to lower prevalence; prenatal ultrasound at gestational week 18–20 detects structural anomalies in about 60% of cases (Gagnon et al., 2009).
Recently, evidence is growing that periconceptional folic acid supplements may have preventive effects on other neurodevelopmental disorders as well. These recent studies can be traced in part to an intriguing finding from the Dutch Famine studies. The Dutch Hunger Winter was a period of severe starvation in West Holland toward the end of the Second World War. Gestational timing of starvation could be estimated because severe famine was relatively brief and food supply was abruptly restored when liberation arrived in May 1945. It was shown that the offspring of women with periconceptional exposure to severe famine—approximately one month before to two months after conception—had an increased risk not only of NTDs, but also of schizoid personality disorder at age 18 and schizophrenia in adulthood (Susser et al., 1996, 1998; Brown and Susser, 2008; Susser and St Clair, 2013). This coincident increase in NTDs and other neurodevelopmental disorders naturally led to the question of whether folic acid supplements could have broader preventive effects. Several studies now support this view, although results are not definitive enough as a basis for intervention. These include results from a large Norwegian prospective pregnancy cohort, where use of prenatal folic acid supplements around the time of conception has been associated with a lower risk of severe language delay (Roth et al., 2011) and autistic disorder (Surén et al., 2012), and a reduced risk of autism spectrum disorders was also observed in a case-control study in California (Schmidt et al., 2012).
Iodine
Iodine deficiency is the leading preventable cause of mental retardation worldwide, and women of childbearing age and infants are at particular risk (Trumpff et al., 2013). Iodine is a micronutrient necessary for the production of thyroid hormones. Thyroid hormones play an essential role in the central nervous system during fetal and early postnatal life. Since iodine was not discussed in the earlier section on fetal immune development, we note that increasing evidence suggests that the immune response is modulated by thyroid hormones (De Vito et al., 2011).
About two billion people ingest too little iodine, and even moderate deficiency is known to lower intelligence. Prevention of iodine deficiency is easily managed by spraying regular table salt with a potassium iodate solution at very low costs. Iodized salts have been a true public health success story, with a rise in the world's household consumed iodized salt increasing from 25% in 1990 to 66% in 2006. Even so, it is presently a concern that iodine deficiency still exists in some regions of the world and has reappeared in some European countries (Vanderpump et al., 2011; Brantsaeter et al., 2013). The World Health Organization recently raised their recommended dietary iodine intake in pregnancy from 200 to 250 g/d (Zimmermann, 2009).
Vitamin D
We have described earlier how vitamin D is pivotal in early immune development and it is also known to be crucial for early skeletal development. It has been proposed, though not proven, that low levels of vitamin D during pregnancy and infancy could increase the risk of neurodevelopmental disorders, and that supplementation could play a role in prevention. An intriguing body of work comprising both rodents and human studies currently supports this view, though no definitive conclusions have been reached yet (Eyles et al., 2013; Pludowski et al., 2013; Yang et al., 2013). Notably, in a recent population-based case control study of 424 individuals with schizophrenia and 424 matched controls, dried blood spots taken at birth were tested for vitamin D levels (McGrath et al., 2010). When vitamin D levels were divided into quintiles, the investigators observed an increased risk of schizophrenia in individuals with vitamin D levels in the three lowest quintiles compared to the fourth quintile. Surprisingly, they also observed an increased risk for schizophrenia in individuals with vitamin D levels in the highest quintile.
Notably, breastfed infants are at especially high risk of vitamin D deficiency due to poor penetrance of vitamin D metabolites in milk (Kovacs, 2013; Thiele et al., 2013). The average level of vitamin D in breast milk is typically 25 IU per liter or less. Fish oil (that commonly contains vitamin D) and other Omega 3 fatty acid supplements taken in infancy have been associated with improved cognitive development, though this evidence is also far from definitive (Auestad et al., 2003; Karr et al., 2011; Meldrum et al., 2012; Luchtman and Song, 2013). The American Academy of Pediatrics recommends that all breastfed infants receive a daily vitamin D supplement of 400 IU, beginning in the first few days of life (Wagner et al., 2008).
Conclusion
Early immune system programming can give rise to changes in the fetal immune system that can persist over the life course. Evidence based on animal, epidemiological and genetic studies suggests that immune dysregulation in the developing brain may play a role in neurodevelopmental disorders, such as autism spectrum disorders and schizophrenia.
The interface between the maternal and fetal compartments plays a central role in how the maternal immune system influences fetal and placental development. The maternal immune system develops an active immune tolerance against fetal-placenta antigens that arises from cell-cell interactions taking place between maternal immune cells resident in the decidua and trophoblast antigens. A range of protective immunoregulatory mechanisms is also critical for the maintenance of a normal pregnancy, development of the fetal immune system, and maternal immunocompetence. The development of the fetal immune system is characterized by the presence of several distinct features that promote fetal active tolerance against both in utero maternal antigens and exogenous antigens, such as infectious agents, vaccines and food antigens. This response pattern has important implications for understanding the impact of prenatal and early life exposure to infections, vaccines, and maternal immune activation.
While well-controlled maternal immune responses play a positive physiological role in fetal immune and nervous system development, an inappropriate maternal immune activation may contribute to an increased risk in the offspring of neurodevelopmental disorders, autoimmune diseases and allergies later in life. Disruption of the fetal immune system can affect the CNS either by local or peripheral processes. Although the pathways by which immune dysfunction can contribute to neurodevelopmental disorders are still not completely understood, the presence of maternal antibodies, immune activation (maternal and fetal) and imbalance of cytokine expression (pro- vs. anti-inflammatory) in the fetal brain can exert a negative impact on brain development if the time of exposure overlaps with major processes in neurodevelopment, such as cell migration, axonal elongation and dendritic tree maturation. Animal studies on maternal immune activation have demonstrated that early life exposure to infections and other factors that lead to immune activation may impose cognitive, behavior and brain morphological abnormalities analogous to findings described in patients with autism, schizophrenia and other psychosis related disorders. These results are supported by epidemiological studies linking maternal prenatal exposure to a wide variety of infections (e.g., influenza, rubella, toxoplasma gondii, etc.) with an increased risk for schizophrenia.
The fetal immune system is particularly vulnerable to environmental insults (e.g., malnutrition, toxins, infections, and stress), mainly during periods when tissue is seeded by precursors of immune cells, which varies depending on the cell type (sensitive window of immune vulnerability). However, deviations in the maternal or fetal immune systems associated with prenatal exposures should be interpreted with caution, as these may be the result of healthy and normal adaptation responses to pregnancy.
Adequate maternal/fetal nutrition is also necessary for the development of fetal and neonatal immune responses and immune cell proliferation, placentation, and the development of oral tolerance. Maternal malnutrition can reduce the supply of nutrients and immune factors to the fetus (via the placenta) and to the infant (via the mammary gland). In particular, maternal micronutrient deficiencies in zinc, fat-soluble vitamins (e.g., vitamins A, D, E) and nutritional factors related to single carbon metabolism (e.g., choline, vitamins B2, B6, B12 and folate) have been shown to play a role in cell-mediated and humoral immune responses. They also have been associated with increased offspring risk for respiratory infections (vitamin D), intestinal inflammation and diarrhea (folate and vitamin A), allergy and asthma (vitamin E and folate) and neurodevelopmental disorders (folate). In addition, food-derived antigens have also been shown to play a role in the development of the fetal immune system (prenatal formation of antigen specific IgE), infant immune system and brain development (oral tolerance and brain-gut-enteric microbiota axis). Prenatal stress and anxiety may also alter aspects of the offspring's innate and adaptive immune systems. However, uncertainty remains about how robust these associations are in humans; the strongest finding is that maternal prenatal stress and anxiety may exacerbate type 2 immune responses already present in the newborn. It has been hypothesized that the impact of maternal prenatal stress and anxiety on the fetal immune system might operate through alteration of the maternal HPA axis, ultimately altering the function (e.g., set point, reactivity) of the child's HPA axis, with a higher set point or greater reactivity of the infant HPA axis predicting a suppressed immune response. Another hypothesis is that immunological changes in the mother associated with maternal prenatal stress and anxiety (e.g., pro-inflammatory cytokines) could cross the placenta and/or alter placental function, consequently exposing the fetus to an elevated immune response early in development.
Interestingly, several examples of nutritional interventions (e.g., encouragement of breastfeeding and specific micronutrient supplements) have been shown to enhance both neurodevelopment and immune development. However, it is still not clear whether nutritional interventions, and, in particular micronutrient supplements (to mother or baby), could reduce the risk of neurodevelopmental disorders by enhancing early development of the immune system. We reported three examples of micronutrients—folate, iodine, and vitamin D—and discussed their proven and potential preventive effects on neurodevelopmental disorders. Future studies are needed to elucidate this relationship, which could contribute to a better understanding of preventive mechanisms and, in turn, perhaps improvements in these interventions.
Based on these findings, we suggest that integrating studies of neurodevelopmental disorders and prenatal exposures (e.g., nutrition and stress) with simultaneous and precise neural and immune system measures can potentially shed light on immunological mechanisms that underlie individual vulnerability or resilience to neurodevelopmental disorders. This research could ultimately contribute to the development of primary preventions and early interventions for mental disorders.
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