Differential effects of docosahexaenoic acid on preterm and term placental pro-oxidant/antioxidant balance

Abstract

Docosahexaenoic acid (DHA) supplementation in pregnancy may confer some clinical benefits; however, this compound can exert pro-oxidant effects. In this study, we investigated the effects of DHA on pro-oxidant/antioxidant balance in term and preterm placental explants, assessing oxidative stress marker concentrations, antioxidant capacity and pro-inflammatory cytokine production. Term (nZ8) and preterm (nZ9) placental explants were exposed to lipopolysaccharide (LPS, 1 ng/ml), DHA (1, 10 and 100 mM), and DHA and LPS simultaneously or pre-treated with DHA for 24 h prior to LPS treatment. The production of malondialdehyde (MDA, lipid peroxidation), 8-hydroxy-2-deoxy guanosine (8-OHdG, oxidative DNA damage) and pro-inflammatory cytokines (tumour necrosis factor a (TNFa), interleukin 6 and interferon-g) and total antioxidant capacity were measured. DHA at a concentration of 100 mM induced oxidative stress in term placentas, while at all the three concentrations, it induced oxidative stress in preterm placentas. DHA and LPS resulted in reduced MDA levels in term (P!0.005) and preterm (PZ0.004) placentas and reduced 8-OHdG levels in preterm placentas (PZ0.035). DHA pre-treatment, but not co-treatment with LPS, reduced 8-OHdG levels (P!0.001) in term placentas. DHA increased antioxidant capacity only in term placentas (P!0.001), with lower antioxidant capacity being observed overall in preterm placentas compared with term placentas (P%0.001). In term placentas, but not in preterm ones, DHA co-treatment and pre-treatment reduced LPS-induced TNFa levels. The ability of DHA to alter placental pro-oxidant/antioxidant balance is dependent on the DHA concentration used and the gestational age of the placental tissue. DHA has a greater capacity to increase oxidative stress in preterm placentas, but it offers greater protection against inflammation-induced oxidative stress in term placentas. This appears to be a result of DHA altering placental antioxidant capacity. These data have implications for the timing and concentration of DHA supplementation in pregnancy.

Maternal dietary omega-3 fatty acids and placental function

“…These findings are consistent with an in vitro study, in which treatment of placental BeWo cells with modest levels of DHA reduced oxidative DNA damage and increased cell survival when challenged by an oxidative insult (Shoji et al 2009). Similarly, in human placental explants, DHA administration reduced LPS-induced oxidative damage and restored antioxidant capacity (Stark et al 2013). Dietary n-3 PUFAs may also reduce ROS generation, given that they increase Ucp2 mRNA expression in mouse white adipose tissue (Hun et al 1999) R148 M L Jones and others placental tissue, being predominantly expressed by the syncytiotrophoblast (Stark et al 2012), although maternal dietary n-3 PUFA supplementation in the rat did not affect placental Ucp2 mRNA expression in our recent study (Jones et al 2013c).…”

“…An in vitro study on placental cells by Shoji et al (2009) demonstrated enhanced lipid peroxidation and reduced cell survival in response to high levels of DHA administration (100 mM), although modest levels (1 or 10 mM) reduced DNA oxidative damage and enhanced cell survival rate. This was recently supported by Stark et al (2013), who found high doses of DHA administration (100 mM) in term placental explants enhanced lipid peroxidation and DNA oxidative damage, while more modest doses (1 or 10 mM) reduced LPS-induced oxidative damage and restored antioxidant capacity. Our in vivo research has found that despite relatively high dietary n-3 PUFA supplementation in pregnant rats, placental levels of the ROS-induced lipid peroxidation marker, F 2 -isoprostanes, were reduced ( Fig.…”

“…Despite this, surprisingly little is known regarding the impact of n-3 PUFAs on placental pro-inflammatory cytokine levels. Stark et al (2013) recently demonstrated that DHA reduces lipopolysaccharide (LPS)-induced tumor necrosis factor a levels in term, but not in preterm, placental explants. In contrast, we found that maternal dietary n-3 PUFA supplementation in rat pregnancy did not suppress placental mRNA expression of key pro-inflammatory cytokines near term (Jones et al 2013b).…”

Altered development and function of the placental regions in preeclampsia and its association with long‐chain polyunsaturated fatty acids

“…The oxidative stress in the placenta has extensively been linked with unsaturated fatty acids. Studies on placental BeWo cell lines, explants, and rats indicate that at lower doses, omega 3 fatty acid (especially DHA) reduces placental oxidative stress and oxidative DNA damage and increases the levels of resolvins, protectins, and total antioxidant capacity . However, in contrast, free radicals are also known to peroxidize LCPUFA, which is injurious to the cells .…”

Reply to Commentary by Strandvik: ‘The development of infants born to obese mothers might be related to omega‐3 fatty acid status’

“…They are likely to be complex as DHA not only has the potential to be beneficial, but also fish oil supplementation has been reported to promote cytokine production and oxidative stress in mice. In addition, the balance of the potential beneficial and adverse effects of DHA appear to vary with the gestational age of the placenta .…”