**2. Omega-3 fatty acids**

Long-chain polyunsaturated fatty acids are fatty acids containing at least 18–20 carbon atoms. They are categorised into two main families according to the position of the first double bond [38], as either omega-3 series or omega-6 series. In omega-3 fatty acids, the first double bond is between the third and fourth carbon atoms (**Table 1**).

The most relevant omega-3 LCPUFAs are alpha-linolenic acid (ALA), docosahexaenoic acid, eicosapentaenoic acid, and docosapentaenoic acid (DPA), while the most relevant omega-6 LCPUFAs are linoleic acid (LA) and arachidonic acid (ARA).

#### **2.1 Synthesis and sources of fatty acids**

In humans, the synthesis of omega-3 and omega-6 fatty acids is limited; they are therefore considered essential fatty acids. LA and ALA are synthesised in large quantities in plants, but humans and other mammals cannot make them from their precursor, oleic acid, because they lack the active enzymes Δ-12 and Δ-15 desaturase [38]. Humans can synthesise other long-chain fatty acids such as ARA, DHA, and EPA from LA and ALA, which are precursors to the omega-6 and omega-3 series, respectively. However, conversion of these fatty acids to DHA, EPA, and ARA is inefficient [39], the most efficient method being to obtain them from the diet. Conversion can vary between sexes and is more efficient in women [40]. It increases during pregnancy and is reduced in newborns [40] due to their lower enzymatic activity.

Both omega-3 and omega-6 LCPUFA syntheses occur via the same pathway of elongation, desaturation, and peroxisomal retroconversion [41]. The most important enzymes in the desaturation processes are Δ-5 and Δ-6 desaturase. The two precursors, LA and ALA, compete for Δ-6 desaturase, but the enzyme has a greater affinity for ALA [40]. Therefore, a high supply of ALA causes a reduction in the synthesis of LA derivatives. In contrast, if LA supply is greater than ALA supply, conversion of ALA to its derivatives is limited. The Western diet contains 10–20 times more omega-6 than omega-3 fatty acids [41]. In addition, the fatty acid content of plasma and many other tissues comprises predominantly omega-6 fatty acids, with the exception of the brain and retina, which are rich in omega-3 [41]. Thus, a high intake of EPA and DHA results in a decrease in tissue levels of ARA and an increase in EPA and DHA, due to enzymatic competition between the two series [42].


**39**

**Figure 1.**

*LCPUFAs food sources.*

*Cytokines and Maternal Omega-3 LCPUFAs Supplementation*

Polyunsaturated fatty acids are found mainly in oily fish and in seed oils. LA, the precursor of omega-6 fatty acids, is present in soybean, corn, and sunflower oils, while ALA, the precursor to omega-3 fatty acids, is found in numerous vegetables, such as linseed, canola, pumpkin seeds, and walnuts. The main dietary sources of EPA and DHA are cold-water oily fish (e.g. sardines, salmon, mackerel, and her-

Despite the benefits of a diet rich in omega-3 fatty acids, there is no consensus on their recommended daily intake. The dietary recommendations from national and international bodies on the intake of omega-3 long-chain fatty acids, in particular EPA and DHA, vary between 200 and 600 mg per day for adults and 40 and 250 mg per day for infants older than 6 months, children, and adolescents [42]. These recommendations are based on the observed association between the omega-3 fatty acid consumption and reduced risk of cardiovascular disease. According to the Nutrition Committee of American Heart Association (AHA Nutrition Committee) recommendations, eating at least two servings of fish per week or 500 mg per day of omega-3 LCPUFAs prevents and reduces the risk of cardiac disease [44, 45]. The expert panel of the European Food Safety Authority (EFSA) recommends an intake of 250 mg per day of omega-3 LCPUFAs, in contrast to the Australian suggested dietary targets of 610 mg EPA and 430 mg DHA per day in adults to reduce cardiovascular risk [38, 46, 47]. To achieve an anti-inflammatory effect, it is recommended to eat between 500 and 1000 mg of omega-3 fatty acids per day [48]. There are also specific recommendations for certain population groups: in pregnant or breastfeeding women, an additional intake of 100–200 mg DHA per day is recommended to compensate for oxidative losses of DHA and its accumulation

*DOI: http://dx.doi.org/10.5772/intechopen.86402*

ring) [43] (**Figure 1**).

in the foetus [42].

**Table 1.**

*Omega-6 and omega-3 long-chain polyunsaturated fatty acids.*

*Cytokines and Maternal Omega-3 LCPUFAs Supplementation DOI: http://dx.doi.org/10.5772/intechopen.86402*

*Maternal and Child Health Matters Around the World*

the umbilical cord blood [32, 37].

**2. Omega-3 fatty acids**

arachidonic acid (ARA).

enzymatic activity.

series [42].

**2.1 Synthesis and sources of fatty acids**

atoms (**Table 1**).

and IL-1 in infants' plasma and a decrease in the Th2 cytokines IL-14 and IL-13 in

Long-chain polyunsaturated fatty acids are fatty acids containing at least 18–20 carbon atoms. They are categorised into two main families according to the position of the first double bond [38], as either omega-3 series or omega-6 series. In omega-3 fatty acids, the first double bond is between the third and fourth carbon

The most relevant omega-3 LCPUFAs are alpha-linolenic acid (ALA), docosahexaenoic acid, eicosapentaenoic acid, and docosapentaenoic acid (DPA), while the most relevant omega-6 LCPUFAs are linoleic acid (LA) and

In humans, the synthesis of omega-3 and omega-6 fatty acids is limited; they are therefore considered essential fatty acids. LA and ALA are synthesised in large quantities in plants, but humans and other mammals cannot make them from their precursor, oleic acid, because they lack the active enzymes Δ-12 and Δ-15 desaturase [38]. Humans can synthesise other long-chain fatty acids such as ARA, DHA, and EPA from LA and ALA, which are precursors to the omega-6 and omega-3 series, respectively. However, conversion of these fatty acids to DHA, EPA, and ARA is inefficient [39], the most efficient method being to obtain them from the diet. Conversion can vary between sexes and is more efficient in women [40]. It increases during pregnancy and is reduced in newborns [40] due to their lower

Both omega-3 and omega-6 LCPUFA syntheses occur via the same pathway of elongation, desaturation, and peroxisomal retroconversion [41]. The most important enzymes in the desaturation processes are Δ-5 and Δ-6 desaturase. The two precursors, LA and ALA, compete for Δ-6 desaturase, but the enzyme has a greater affinity for ALA [40]. Therefore, a high supply of ALA causes a reduction in the synthesis of LA derivatives. In contrast, if LA supply is greater than ALA supply, conversion of ALA to its derivatives is limited. The Western diet contains 10–20 times more omega-6 than omega-3 fatty acids [41]. In addition, the fatty acid content of plasma and many other tissues comprises predominantly omega-6 fatty acids, with the exception of the brain and retina, which are rich in omega-3 [41]. Thus, a high intake of EPA and DHA results in a decrease in tissue levels of ARA and an increase in EPA and DHA, due to enzymatic competition between the two

Arachidonic acid (ARA) C20:4ω-6

Eicosapentaenoic acid (EPA) C20:5 ω-3 Docosahexaenoic acid (DHA) C22:6 ω-3 Docosapentaenoic acid (DPA) C22:5 ω-3

Omega-6 fatty acids Linoleic acid (LA) C18:2 ω-6

*Omega-6 and omega-3 long-chain polyunsaturated fatty acids.*

Omega-3 fatty acids Alpha linolenic acid (ALA) C18:3 ω-3

**38**

**Table 1.**

Polyunsaturated fatty acids are found mainly in oily fish and in seed oils. LA, the precursor of omega-6 fatty acids, is present in soybean, corn, and sunflower oils, while ALA, the precursor to omega-3 fatty acids, is found in numerous vegetables, such as linseed, canola, pumpkin seeds, and walnuts. The main dietary sources of EPA and DHA are cold-water oily fish (e.g. sardines, salmon, mackerel, and herring) [43] (**Figure 1**).

Despite the benefits of a diet rich in omega-3 fatty acids, there is no consensus on their recommended daily intake. The dietary recommendations from national and international bodies on the intake of omega-3 long-chain fatty acids, in particular EPA and DHA, vary between 200 and 600 mg per day for adults and 40 and 250 mg per day for infants older than 6 months, children, and adolescents [42]. These recommendations are based on the observed association between the omega-3 fatty acid consumption and reduced risk of cardiovascular disease. According to the Nutrition Committee of American Heart Association (AHA Nutrition Committee) recommendations, eating at least two servings of fish per week or 500 mg per day of omega-3 LCPUFAs prevents and reduces the risk of cardiac disease [44, 45]. The expert panel of the European Food Safety Authority (EFSA) recommends an intake of 250 mg per day of omega-3 LCPUFAs, in contrast to the Australian suggested dietary targets of 610 mg EPA and 430 mg DHA per day in adults to reduce cardiovascular risk [38, 46, 47]. To achieve an anti-inflammatory effect, it is recommended to eat between 500 and 1000 mg of omega-3 fatty acids per day [48]. There are also specific recommendations for certain population groups: in pregnant or breastfeeding women, an additional intake of 100–200 mg DHA per day is recommended to compensate for oxidative losses of DHA and its accumulation in the foetus [42].

**Figure 1.** *LCPUFAs food sources.*

There are few data on the adverse effects of long-term high-dose DHA supplementation. The EFSA expert panel considers DHA dietary supplementation of up to 1 g per day to not pose a risk in the general population. In a systematic review [1] of studies on DHA supplements during pregnancy, it was concluded that an intake of 1–2.7 g per day of omega-3 LCPUFAs is not harmful.

#### **2.2 General functions of fatty acids**

#### *2.2.1 Cell membrane structure and function*

Omega-3 polyunsaturated fatty acids are important structural components of cell membranes, where they are present as membrane phospholipids (esterified fatty acids) or as free molecules [49]. The incorporation of free polyunsaturated fatty acids into membrane phospholipids appears to alter the physical properties of the membranes. They can influence the structure of membrane phospholipids, reducing the van der Waals interactions [50].

They contribute to several membrane functions such as fluidity, permeability, enzymatic and receptor activity, gene expression, and signal transduction [41, 42, 51]. The changes in permeability appear to depend directly on the degree of fatty acid desaturation [49]. EPA and DHA are of particular biological importance.

#### *2.2.2 Visual and neurological function*

The nervous system takes a long time to develop and mature, but there are many crucial events that occur during pregnancy and the first years of life. The brain grows rapidly between week 20 of gestation and 2 years of age, increasing in size by 64% during the first 3 months of life [52]. In these stages there is a period termed the *window of sensitivity*, during which certain nutrients or stimuli can influence and promote neurological development and functional brain capacity. Several nutrients have been described to play a crucial role in the development of the nervous system, including choline, iron, zinc, and long-chain fatty acids such as nervonic acid and DHA [53–55].

DHA forms part of the structural lipids of cell membranes, particularly the phospholipids found in the nervous tissue and the retina [38], where high levels of DHA have been found, primarily in the grey matter and photoreceptors; it is therefore thought to be essential for proper neurological and visual development [9, 35, 56–58]. Similarly, high levels of omega-3 polyunsaturated fatty acids have been found in the basal ganglia, frontal cortex, occipital cortex, hippocampus, and thalamus in studies performed on the young of baboons and rats, which suggests that they affect sensory-motor integration and memory [59–61]. Cerebral development affects cognitive, social, and motor functions and communication. Stimulation and optimal nutrition [62] are essential. It has been demonstrated that babies who receive adequate quantities of omega-3 LCPUFAs, especially of DHA, show better development in these areas [63–68], so DHA is thought to be essential for the growth and function of neuronal and visual tissue [53]. These benefits continue beyond childhood [64, 69], and DHA is recommended as an essential dietary component in breastfeeding women and in children, to support brain development [54].

DHA appears to have important properties as a free radical scavenger, protecting against oxidative damage in developing and adult brains. It also has a role in neuronal plasticity, a process that allows the replacement of damaged neuronal circuits and reorganisation of existing ones. It combines with glycerophosphocholine and phosphatidylserine to promote the formation of membrane phospholipids for the growth of nerve cells [55] and has also been observed to play a role in cell

**41**

*Cytokines and Maternal Omega-3 LCPUFAs Supplementation*

migration during brain development [70]. Animal studies have demonstrated that DHA supplementation during pregnancy and breastfeeding is associated with an increased density of dendritic spines in the hippocampus [71] and of some synaptic proteins in the brains of weaned rats, while DHA deficiency has been associated with smaller neuronal soma [72] and altered synaptic vesicle density and neuronal growth and survival. Another study has demonstrated that supplementation with DHA significantly increases neuronal growth and synaptogenesis and increases levels of pre- and postsynaptic proteins involved in synaptic transmission and longterm potentiation, which is associated with improved synaptic function [73].

Omega-3 fatty acids are considered effective in the prevention of many diseases due to their antioxidant effects [74], yet there remains some debate on the subject. DHA, being a highly unsaturated fatty acid, is extremely susceptible to lipid peroxidation. Therefore, it is essential to ensure that LCPUFA supplements are safe, as they may generate free radicals that can affect the tissues. However, several studies in children found no abnormalities in baseline levels of peroxidised lipids nor in antioxidant enzymatic activity. Randomised studies in which up to 1 g per day of DHA or 2–7 g per day of omega-3 LCPUFAs was given found no adverse effects,

Pregnancy is a state in which there is a high metabolic demand and increased production of free radicals. Pregnant women have been observed to have higher levels of free radical damage than non-pregnant women. Labour also involves increased oxidative damage in both mother and baby, being even higher in premature newborns [77, 78]. Studies carried out in animals have found increased activity of superoxide dismutase (SOD), an important antioxidant enzyme, in rat brains following post-natal DHA supplementation [79]. In a subsequent study in pregnant women, it was suggested that consumption of fish oil during pregnancy could have antioxidant effects during this period although the results were not conclusive [80].

Several studies have demonstrated the beneficial effect of fatty acids in inflammatory [81, 82] and autoimmune diseases such as systemic lupus erythematosus [43], asthma, cystic fibrosis [83], chronic obstructive pulmonary disease (COPD) [38], rheumatoid arthritis [81], multiple sclerosis [33, 38, 84, 85], ulcerative colitis [86], Crohn's disease [81], and type 2 diabetes mellitus [33, 87].

The beneficial effects of omega-3 fatty acids on cardiovascular disease are widely known [88, 89]. Omega-3 LCPUFAs not only reduce triglyceride levels [90–93] but also reduce the production of chemotactic agents, growth factors, adhesion molecules, inflammatory eicosanoids and inflammatory cytokines, decrease blood pressure, increase nitric oxide production, improve endothelial relaxation and vascular compliance, and reduce thrombus formation and cardiac arrhythmias [94, 95]. Although the mechanisms of their protective effects are not fully established, it has been proposed that they may be due to the anti-inflammatory effects of these fatty acids on blood vessel walls [95], their aforementioned lipid-lowering effect, the regulated production of less potent eicosanoids, and the inhibition of pro-inflammatory cytokine production [89, 94], mechanisms which have also been

Fish oil supplementation has also been shown to be beneficial in oncological processes [38] and is associated with a reduced incidence of metastatic breast cancer [33]. Its benefits have also been demonstrated in patients with colorectal

shown to exert benefits in peripheral vascular disease [94].

*DOI: http://dx.doi.org/10.5772/intechopen.86402*

*2.2.3 DHA and oxidative stress*

including in pregnant women [75, 76].

*2.2.4 Other benefits and disease prevention*

migration during brain development [70]. Animal studies have demonstrated that DHA supplementation during pregnancy and breastfeeding is associated with an increased density of dendritic spines in the hippocampus [71] and of some synaptic proteins in the brains of weaned rats, while DHA deficiency has been associated with smaller neuronal soma [72] and altered synaptic vesicle density and neuronal growth and survival. Another study has demonstrated that supplementation with DHA significantly increases neuronal growth and synaptogenesis and increases levels of pre- and postsynaptic proteins involved in synaptic transmission and longterm potentiation, which is associated with improved synaptic function [73].
