The Impact of Oxidative Stress of Environmental Origin on the Onset of Placental Diseases

Abstract

Oxidative stress (OS) plays a pivotal role in placental development; however, abnormal loads in oxidative stress molecules may overwhelm the placental defense mechanisms and cause pathological situations. The environment in which the mother evolves triggers an exposure of the placental tissue to chemical, physical, and biological agents of OS, with potential pathological consequences. Here we shortly review the physiological and developmental functions of OS in the placenta, and present a series of environmental pollutants inducing placental oxidative stress, for which some insights regarding the underlying mechanisms have been proposed, leading to a recapitulation of the noxious effects of OS of environmental origin upon the human placenta.

Keywords: DNA methylation; P38MAPK; environmental pollution; heavy metals; hypertensive disorders of pregnancy; placenta; placental diseases.

Figure 1

Schematic representation of a placental villous tree during human pregnancy. These tree-like structures are composed of an outermost syncytiotrophoblast (STB) layer in pink, cytotrophoblast (light purple) and fetal stromal cells (dark purple). Fetal capillaries invade these structures to obtain nutrients and exchange gases. Between each placental villous, maternal lacunae are visible, where the maternal spiral arteries potentially deliver the maternal blood. In the early stages of pregnancy, this supply is blocked by extravillous trophoblast plugs, leading to a low oxygen concentration (2–3% O₂). Expression of hypoxia-inducible transcription factors (HIF) stimulates the expression of the vascular endothelial growth factor (VEGF), which stimulates the production of nitric oxide (NO). NO stimulates, at the same time, VEGF functions as a pro-angiogenic molecule. Once these plugs are removed around week 12 of pregnancy, the maternal blood bathes the lacunae, allowing the interchange of nutrients and gases between the mother and the foetus. This highly oxygenated blood increases the oxygen tension to normoxic levels (6–8% O₂ in the tissue context), increasing the STB mitochondrial activity and thus, the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Increased OS induces the expression of antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx). Oxygen tension stimulates the placental inducible growth factor (PIGF) implicated expression in endothelial growth and angiogenesis.

Figure 2

A cartoon emphasizing the pivotal role of P38MAPK(MAPK11) in the sensing of OS and the direct or indirect activation of various transcription factors. This is an oversimplification since this factor, once inside the nucleus, can also modulate chromatin structure through action upon structural components of the chromatins such as HMGN1 or Histone H3. This drawing is a simplification from [89].

Figure 3

A brief graphic summary of the mechanistic impacts of environmental exposure through oxidative stress alterations in the human placenta, as detailed in the text of this review. At the center of this graph is the mitochondria which is the major producer of oxidative stress (ROS = Reactive Oxygen Species, and RNS = Reactive Nitrogen Species). The red dashed arrows relate to the generation of oxidative stress; the box on the upper left summarizes the antioxidant mechanisms that will fight against oxidative stress (the balance GSH/GSSG, the Superoxide Dismutases, the Glutathione peroxidases, the Catalase). The effect of OS on biomolecules appears on proteins, DNA and lipids as shown in the hexagon in the middle of the figure, with specific chemical modifications. Below, the placenta on which this review is focused is presented, part of the oxidative stress response being triggered in this organ by the activation of the P38/MAPK pathway. In black are the sources of oxidative stress in the human placenta that are described in this paper (Metalloids and Metals, Tobacco smoke and Atmospheric particulate matter). In Blue boxes at the right part of the figure are presented specific chemicals that are part of the placental regulation of oxidative stress, acting either on ROS production or modulation of ROS detoxification that is further detailed in the text. Other abbreviations: ETC = Electron Transport Chain, NOX = Nitric Oxidases, sFLT1 = Soluble FMS-Like Tyrosine kinase 1, sENG = soluble Endoglin, CO = Carbon Monoxide, TOCP = Tri-ortho-cresyl phosphate.