## 4 Discussion
### Biological Plausibility  
Studies that have accumulated over the recent years have shown that development and maintenance of good uteroplacental circulation in the pregnant mother is a major precondition for a healthy pregnancy outcome, as the latter is highly dependent on a well-working placenta. Healthy placenta can transfer enough oxygen and nutrients that are required for healthy fetal development and energy transfer from the maternal body to the fetus [47; 48]. Developing fetuses are especially vulnerable to adverse effects of environmental pollutants because prenatal exposure to toxic and irritant pollutants can cause inflammation in the fetal lungs [49]. However, the mechanisms underlying many of the adverse effects on fetuses related to air pollutants remain so far unclear. NO\({}_{2}\) and SO\({}_{2}\) exposures are considered to have some toxic effects on the functional and developmental growth of exposed fetuses. The mechanisms underlying such an effect include stimulation of the formation of cell-damaging lipid peroxides and reduction of the maternal antioxidant reserves [50; 51].  
The effects that both particulate matter and carbon monoxide have on birth weight have been reported and explained by transfer of these pollutants from the mother to the lungs of the growing fetus via the placenta [52]. The amount of oxygen available in the placenta for the fetus will be compromised if an increased amount of CO reduces the oxygen-carrying capacity of maternal hemoglobin, which is responsible for delivering oxygen into the fetal circulation [53; 54]. Maternal exposure to PM has been reported to cause oxidative stress in the mother, leading to pulmonary and placental inflammation, which alters blood coagulation factors, and this triggers hemodynamic responses. The latter, in turn, reduce birth weight through impaired transplacental oxygen and nutrient exchange [55]. PM can also cause oxidative inflammation in the lungs of the mother and placenta, and such inflammation may lead to reduction in the fetal growth [56].  
Concerning inflammatory responses, particulate matter inhaled by the mother can induce a strong adverse reaction in the maternal body. It has been reported that PM\({}_{2.5}\)--fine granulate PM--becomes enriched in the maternal blood stream when inhaled or ingested and moves through the placenta into the embryo, where it can seriously interfere with embryonic development. It can cause apoptosis and interfere with apoptotic pathways that are active during embryonic development [57]. In general, there are three different pathways. One is extrinsic and mediated through \"death receptors\", i.e., directed through influence outside of the cells and the tissues; the second one is intrinsic and involves mitochondria; and the third one is intrinsic as well, based on cellular stressors that affect the endoplasmic reticulum (ER). Using primary fetal alveolar cells, [PERSON] et al. (2014) [58] demonstrated that exposure of these cells to fine particulate matter, contained in cooking oil fumes, can upregulate proapoptotic signaling mediators and can downregulate antiapoptotic ones. Specifically, the extrinsic death receptor pathway and the intrinsic mitochondrial pathways were activated [58]. In another study, cultured rat embryos experienced growth retardation when exposed to PM\({}_{2.5}\). The authors found both an activation of apoptotic pathways as well as cell cycle arrest between G0 and G1 phase and provided evidence that reactive oxygen species (ROS), JNK, and ERK signaling was also involved in these processes; this led not only to a shortening in the embryo's length and reduction of the yolk sac diameter but also to a reduction in the number of somites [59].