Chuturgoon, Anil Amichund.Anderson, Samantha Mary.2019-08-292019-08-2920172017https://researchspace.ukzn.ac.za/handle/10413/16422Doctor of Philosophy in Medical Biochemistry and Chemical Pathology. University of KwaZulu-Natal. Durban, 2017.Living or working within an unhealthy environment is attributed to 12.6 million deaths worldwide and 2.2 million deaths in Africa. Ambient air pollution (AAP) exposure is amongst the major contributors of environmental and air quality decay. Durban South Africa (SA) is a rapidly developing city that requires increased infrastructure, transportation, and energy production to support the growing urban population. This leads to air quality degradation, in addition to the heavy burden of human immunodeficiency virus (HIV) and obesity SA faces increase the susceptibility of pathological conditions including respiratory diseases and adverse birth outcomes. Infants in utero are particularly vulnerable to adverse AAP effects, attributed to oxidative stress (OS), inflammation and genetic susceptibility, due to their biological vulnerability, sensitivity to their environment and rapid differentiation and growth. South Durban (SD) comprises a complex mix of dense residential settlements and heavily industrialised areas with high levels of air pollution (AP). This makes SD an ideal location to investigate the effects of AAP, in particular, traffic-related AP (atmospheric oxides of nitrogen (NOx)), on OS and endoplasmic reticulum (ER) stress responses within third trimester pregnant women. A comparison sample of pregnant women, located within north Durban (ND) of similar socio-economic status were used for this study. The susceptibility of OS markers, including 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-OHdG) DNA adducts, lipid peroxidation (LP) and nitric oxide (NO) levels, on adverse birth outcomes, including low birthweight (LBW) and pre-term birth (PTB), were also determined. Additional risk factors such as HIV, obesity and single nucleotide polymorphisms (SNP) within genes of the antioxidant response pathway were investigated for OS and adverse birth outcome susceptibility. Atmospheric NOx pollution data were obtained from land use regression modelling that was previously reported. Atmospheric NOx and maternal serum 8-OHdG adducts were significantly elevated within SD living pregnant women. This induction of DNA damage was found to be the direct consequence of NOx exposure. Pregnant women carrying the variant and wild-type (wt) genotypes of glutathione S transferase (GST) P1 and M1 SNPs, respectively, increased the susceptibility of NOx induced OS. Exposure to increased NOx levels significantly reduced the gestational age (GA) of these pregnant women, with increased susceptibility for mothers carrying male neonates. The wt 8-oxoguanine glycosylase 1 (OGG1) Ser326Cys genotype was found to be associated with both HIV and obesity. Therefore pregnant women infected with HIV (HIV+) and carrying the wt genotype significantly increased the risk for HIV associated LBW and PTB. In addition, living within SD and being exposed to higher levels of AAP significantly increased the susceptibility for PTB. Comorbid HIV and obesity were identified as additional risk factors for birthweight (BW) reduction. Increased maternal serum NO levels were observed within HIV+ women, with reciprocal activity on malondialdehyde (MDA) levels. Increased levels of NO directly reduced BW, especially for HIV+ and SD living women. This suggests NO may play a key role in LBW aetiology as a consequence of HIV infection and traffic-related AP. HIV was shown to differentially modulate MDA’s effect on neonatal BW. Exposure to increased levels of NOx and HIV infection induced the expression of microRNA (miR)-144, which was shown to negatively regulate nuclear factor (erythroid-derived 2)-like 2 (Nrf2). This transcription factor, Nrf2, was shown to significantly increase antioxidant gene expressions. Therefore the induction of miR-144 was implicated as a mechanism for increased OS due to HIV and NOx exposure. In addition, elevated ER stress genes were observed within HIV negative SD living patients. Hence, exposure to higher levels of AAP within SD led to increased ER stress, which may act reciprocally on the induction of ROS leading to increased OS. These findings indicate that exposure to atmospheric NOx, elevated AAP levels within SD and exposure to HIV infection resulted in increased OS with increased susceptibility towards adverse birth outcomes within pregnant women. Further studies into the mechanisms proposed within a larger population including multiple pollutants and gene interactions may give additional insight into the aetiology of adverse birth outcomes as a consequence of AAP exposure.enAmbient air pollution.Durban south industrial basin.Reactive oxygen species.Adverse birth outcomes and oxidative.Thesis