*2.2.3 DHA and oxidative stress*

*Maternal and Child Health Matters Around the World*

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*

reducing the van der Waals interactions [50].

*2.2.2 Visual and neurological function*

nervonic acid and DHA [53–55].

tion [49]. EPA and DHA are of particular biological importance.

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

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,

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 desatura-

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

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

**40**

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, including in pregnant women [75, 76].

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].

### *2.2.4 Other benefits and disease prevention*

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

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 cancer [96], with an observed reduction in inflammatory markers such as interleukin-6 (IL-6) in patients taking omega-3 fatty acid supplements, although these benefits are dependent on the duration, dose, and route of supplementation and the specific type of oncological treatment received. Its effects in leukaemia, lymphoma, neuroblastoma, glioblastoma, and lung, cervical, pancreatic, bladder, and ovarian cancer [97] have also been studied. The proposed mechanisms by which LCPUFAs act as adjuvants in cancer-specific treatments relate to their antitumour properties: they are anti-inflammatory [98], antiproliferative, pro-apoptotic, anti-invasive, and antimetastatic [99] and have epigenetic-regulatory effects [100]. Further studies are required to establish the therapeutic recommendations for EPA and DHA in oncological processes [97].
