Perfluoroalkyl substances (PFASs) are widespread industrial pollutants that are extremely persistent in the environment. Animal studies have indicated that in-utero PFAS exposures can affect fetal growth, but findings from human studies are inconclusive. Few human studies have sufficient sample size to study the influence of PFASs on adverse birth outcomes. Here, we conducted a pooled analysis using data of 3,535 mothers and infant pairs using three sub-samples originating from the Danish National Birth Cohort (DNBC), and we evaluated the associations between prenatal PFASs exposures and birth outcomes. Maternal plasma concentrations of six types of PFASs in early pregnancy (around 8.7 gestational weeks) were studied. We found that each LN-ng/ml increase in PFOS, PFOA, PFNA and PFHpS was associated with a 65g, 51g, 52g or 56g decrease in birth weight. Moreover, we also found that prenatal PFOS, PFHpS, PFDA levels were associated with the risks for preterm birth (< 37 completed gestational week). Our findings strengthen the evidence that in-utero PFAS exposures may affect fetal growth. These findings raise concerns considering the ubiquitous contamination of PFASs in the environment. Public health strategies to prevent or lower PFASs exposures in pregnant women are needed.

Prenatal exposures to ambient particulate matter (PM2.5) from traffic may generate oxidative stress, and thus contribute to adverse birth outcomes including preterm birth (PTB) and term low birth weight (TLBW), but little is known about the effects of exposure to specific constituents of PM2.5 or mechanisms that contribute to these outcomes. Furthermore, numerous studies have reported the effects of maternal diet on adverse birth outcomes, but few population-based studies evaluated maternal dietary patterns and placental growth. In this dissertation, we investigated health effects of prenatal exposures to PM2.5 from brake and tire wear, and how the maternal diet affects placental growth during pregnancy.First, in a birth cohort of 285,614 singletons born in Los Angeles County, California during 2017-2019, we estimated increased risks for PTB and TLBW per interquartile range (IQR) exposure increment of metals and oxidative potential metrics that were robust to adjustment for PM2.5 mass. Second, we investigated whether these PM2.5 constituents affect levels of oxidative stress biomarkers (malondialdehyde (MDA), 8-hydroxy-2’-deoxyguanosine (8-OHdG)) using urine samples collected up to three times during pregnancy in a cohort of pregnant women recruited from antenatal clinics at the University of California Los Angeles (UCLA). 8-OHdG concentrations in mid-pregnancy increased per IQR increase in PM2.5 mass and black carbon. The brake wear marker (barium) and the oxidative potential metrics were associated with increased urinary MDA concentration in early pregnancy, but 95% CIs included the null. Last, using the same cohort recruited from UCLA, we found placental volume in mid-pregnancy was associated with a higher score of Healthy Eating Index-2015 (≥ median), and a higher placenta weight at delivery was associated with a higher score of Alternate Mediterranean Diet (≥ median). Our results indicate that reduction of PM2.5 mass only may not be sufficient to protect the most vulnerable pregnant women from adverse effects due to traffic source exposures. Our findings provide novel insights into potential biological mechanism of PM2.5 exposure related health effect among pregnant women. Moreover, our study suggests that placentation and adverse pregnancy outcomes can be addressed by nutritional measures and interventions in early to mid-pregnancy.

Most human genes exhibit alternative splicing, but not all alternatively spliced transcripts produce functional proteins. Computational and experimental results indicate that a substantial fraction of alternative splicing events in humans result in mRNA isoforms that harbor a premature termination codon (PTC). These transcripts are predicted to be degraded by the nonsense-mediated mRNA decay (NMD) pathway. One explanation for the abundance of PTC-containing isoforms is that they represent splicing errors that are identified and degraded by the NMD pathway. Another potential explanation for this startling observation is that cells may link alternative splicing and NMD to regulate the abundance of mRNA transcripts. This mechanism, which we call "Regulated Unproductive Splicing and Translation" (RUST), has been experimentally shown to regulate expression of a wide variety of genes in many organisms from yeast to human. It is frequently employed for autoregulation of proteins that affect the splicing process itself. Thus, alternative splicing and NMD act together to play an important role in regulating gene expression.

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