Attenuation of Polycyclic Aromatic Hydrocarbon (PAH)-Induced Carcinogenesis and Tumorigenesis by Omega-3 Fatty Acids in Mice In Vivo.

Lung cancer is the leading cause of cancer death worldwide. Polycyclic aromatic hydrocarbons (PAHs) are metabolized by the cytochrome P450 (CYP)1A and 1B1 to DNA-reactive metabolites, which could lead to mutations in critical genes, eventually resulting in cancer. Omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are beneficial against cancers. In this investigation, we elucidated the mechanisms by which omega-3 fatty acids EPA and DHA will attenuate PAH-DNA adducts and lung carcinogenesis and tumorigenesis mediated by the PAHs BP and MC. Adult wild-type (WT) (A/J) mice, Cyp1a1-null, Cyp1a2-null, or Cyp1b1-null mice were exposed to PAHs benzo[a]pyrene (BP) or 3-methylcholanthrene (MC), and the effects of omega-3 fatty acid on PAH-mediated lung carcinogenesis and tumorigenesis were studied. The major findings were as follows: (i) omega-3 fatty acids significantly decreased PAH-DNA adducts in the lungs of each of the genotypes studied; (ii) decreases in PAH-DNA adduct levels by EPA/DHA was in part due to inhibition of CYP1B1; (iii) inhibition of soluble epoxide hydrolase (sEH) enhanced the EPA/DHA-mediated prevention of pulmonary carcinogenesis; and (iv) EPA/DHA attenuated PAH-mediated carcinogenesis in part by epigenetic mechanisms. Taken together, our results suggest that omega-3 fatty acids have the potential to be developed as cancer chemo-preventive agents in people.

Role of Human NADPH Quinone Oxidoreductase (NQO1) in Oxygen-Mediated Cellular Injury and Oxidative DNA Damage in Human Pulmonary Cells.

Supplemental oxygen administration is frequently used in premature infants and adults with pulmonary insufficiency. NADPH quinone oxidoreductase (NQO1) protects cells from oxidative injury by decreasing reactive oxygen species (ROS). In this investigation, we tested the hypothesis that overexpression of NQO1 in BEAS-2B cells will mitigate cell injury and oxidative DNA damage caused by hyperoxia and that A-1221C single nucleotide polymorphism (SNP) in the NQO1 promoter would display altered susceptibility to hyperoxia-mediated toxicity. Using stable transfected BEAS-2B cells, we demonstrated that hyperoxia decreased cell viability in control cells (Ctr), but this effect was differentially mitigated in cells overexpressing NQO1 under the regulation of the CMV viral promoter, the wild-type NQO1 promoter (NQO1-NQO1), or the NQO1 promoter carrying the SNP. Interestingly, hyperoxia decreased the formation of bulky oxidative DNA adducts or 8-hydroxy-2'-deoxyguanosine (8-OHdG) in Ctr cells. qPCR studies showed that mRNA levels of CYP1A1 and NQO1 were inversely related to DNA adduct formation, suggesting the protective role of these enzymes against oxidative DNA injury. In SiRNA experiments entailing the NQO1-NQO1 promoter, hyperoxia caused decreased cell viability, and this effect was potentiated in cells treated with CYP1A1 siRNA. We also found that hyperoxia caused a marked induction of DNA repair genes DDB2 and XPC in Ctr cells, supporting the idea that hyperoxia in part caused attenuation of bulky oxidative DNA lesions by enhancing nucleotide excision repair (NER) pathways. In summary, our data support a protective role for human NQO1 against oxygen-mediated toxicity and oxidative DNA lesions in human pulmonary cells, and protection against toxicity was partially lost in SNP cells. Moreover, we also demonstrate a novel protective role for CYP1A1 in the attenuation of oxidative cells and DNA injury. Future studies on the mechanisms of attenuation of oxidative injury by NQO1 should help in developing novel approaches for the prevention/treatment of ARDS in humans.

The role of cytochrome P450 (CYP) enzymes in hyperoxic lung injury.

INTRODUCTION: Hyperoxic lung injury is a condition that can occur in patients in need of supplemental oxygen, such as premature infants with bronchopulmonary dysplasia or adults with acute respiratory distress syndrome. Cytochrome P450 (CYP) enzymes play critical roles in the metabolism of endogenous and exogenous compounds. AREAS COVERED: Through their complex pathways, some subfamilies of these enzymes may contribute to or protect against hyperoxic lung injury. Oxidative stress from reactive oxygen species (ROS) production is most likely a major contributor of hyperoxic lung injury. CYP1A enzymes have been shown to protect against hyperoxic lung injury while CYP1B enzymes seem to contribute to it. CYP2J2 enzymes help protect against hyperoxic lung injury by triggering EET production, thereby, increasing antioxidant enzymes. The metabolism of arachidonic acid to ω-terminal hydroxyeicosatetraenoic acid (20-HETEs) by CYP4A and CYP4F enzymes could impact hyperoxic lung injury via the vasodilating effects of 20-HETE. CYP2E1 and CYP2A enzymes may contribute to the oxidative stress in the lungs caused by ethanol- and nicotine-metabolism, respectively. EXPERT OPINION: Overall, the CYP enzymes, depending upon the isoform, play a contributory or protective role in hyperoxic lung injury, and are, therefore, ideal candidates for developing drugs that can treat oxygen-mediated lung injury.

Pilot-Scale Pyrolytic Remediation of Crude-Oil-Contaminated Soil in a Continuously-Fed Reactor: Treatment Intensity Trade-Offs.

Pyrolytic treatment offers the potential for the rapid remediation of contaminated soils. However, soil fertility restoration can be highly variable, underscoring the need to understand how treatment conditions affect soil detoxification and the ability to support plant growth. We report here the first pilot-scale study of pyrolytic remediation of crude-oil-contaminated soil using a continuously fed rotary kiln reactor. Treatment at 420 °C with only 15 min of residence time resulted in high removal efficiencies for both total petroleum hydrocarbons (TPH) (99.9%) and polycyclic aromatic hydrocarbons (PAHs) (94.5%) and restored fertility to clean soil levels (i.e., Lactuca sativa biomass dry weight yield after 21 days increased from 3.0 ± 0.3 mg for contaminated soil to 8.8 ± 1.1 mg for treated soil, which is similar to 9.0 ± 0.7 mg for uncontaminated soil). Viability assays with a human bronchial epithelial cell line showed that pyrolytic treatment effectively achieved detoxification of contaminated soil extracts. As expected, TPH and PAH removal efficiencies increased with increasing treatment intensity (i.e., higher temperatures and longer residence times). However, higher treatment intensities decreased soil fertility, suggesting that there is an optimal system-specific intensity for fertility restoration. Overall, this study highlights trade-offs between pyrolytic treatment intensity, hydrocarbon removal efficiency, and fertility restoration while informing the design, optimization, and operation of large-scale pyrolytic systems to efficiently remediate crude-oil-contaminated soils.

Can maternal DHA supplementation offer long-term protection against neonatal hyperoxic lung injury?

The effect of adverse perinatal environment (like maternal infection) has long-standing effects on many organ systems, including the respiratory system. Use of maternal nutritional supplements is an exciting therapeutic option that could be used to protect the developing fetus. In a recent issue of the journal, Ali and associates (Ali M, Heyob KM, Velten M, Tipple TE, Rogers LK. Am J Physiol Lung Cell Mol Physiol 309: L441-L448, 2015) specifically look at maternal docosahexaenoic acid (DHA) supplementation and its effect on chronic apoptosis in the lung in a mouse model of perinatal inflammation and postnatal hyperoxia. Strikingly, the authors show that pulmonary apoptosis was augmented even 8 wk after the hyperoxia-exposed mice had been returned to room air. This effect was significantly attenuated in mice that were subjected to maternal dietary DHA supplementation. These findings are novel, significantly advance our understanding of chronic effects of adverse perinatal and neonatal events on the developing lung, and thereby offer novel therapeutic options in the form of maternal dietary supplementation with DHA. This editorial reviews the long-term effects of adverse perinatal environment on postnatal lung development and the protective effects of dietary supplements such as DHA.

Effects of dietary fish oil on the depletion of carcinogenic PAH-DNA adduct levels in the liver of B6C3F1 mouse.

Many carcinogenic polycyclic aromatic hydrocarbons (PAHs) and their metabolites can bind covalently to DNA. Carcinogen-DNA adducts may lead to mutations in critical genes, eventually leading to cancer. In this study we report that fish oil (FO) blocks the formation of DNA adducts by detoxification of PAHs. B6C3F1 male mice were fed a FO or corn oil (CO) diet for 30 days. The animals were then treated with seven carcinogenic PAHs including benzo(a)pyrene (BaP) with one of two doses via a single intraperitoneal injection. Animals were terminated at 1, 3, or 7 d after treatment. The levels of DNA adducts were analyzed by the (32)P-postlabeling assay. Our results showed that the levels of total hepatic DNA adducts were significantly decreased in FO groups compared to CO groups with an exception of low PAH dose at 3 d (P = 0.067). Total adduct levels in the high dose PAH groups were 41.36±6.48 (Mean±SEM) and 78.72±8.03 in 10(9) nucleotides (P = 0.011), respectively, for the FO and CO groups at 7 d. Animals treated with the low dose (2.5 fold lower) PAHs displayed similar trends. Total adduct levels were 12.21±2.33 in the FO group and 24.07±1.99 in the CO group, P = 0.008. BPDE-dG adduct values at 7 d after treatment of high dose PAHs were 32.34±1.94 (CO group) and 21.82±3.37 (FO group) in 10(9) nucleotides with P value being 0.035. Low dose groups showed similar trends for BPDE-dG adduct in the two diet groups. FO significantly enhanced gene expression of Cyp1a1 in both the high and low dose PAH groups. Gstt1 at low dose of PAHs showed high levels in FO compared to CO groups with P values being 0.014. Histological observations indicated that FO played a hepatoprotective role during the early stages. Our results suggest that FO has a potential to be developed as a cancer chemopreventive agent.

Attenuation of oxygen-induced abnormal lung maturation in rats by retinoic acid: possible role of cytochrome P4501A enzymes.

Supplemental oxygen is frequently used in the treatment of infants having pulmonary insufficiency, but prolonged hyperoxia may contribute to the development of bronchopulmonary dysplasia in these infants. Cytochrome P4501A enzymes have been implicated in hyperoxic lung injury. Retinoic acid (RA) plays a key role in lung development. Here, we tested the hypotheses that newborn rats exposed to a combination of RA and hyperoxia would be less susceptible to lung injury than those exposed to hyperoxia only and that modulation of CYP1A enzymes by RA contribute to the beneficial effects of RA against hyperoxic lung injury. Newborn rats exposed to hyperoxia for 7 days showed higher lung weight/body weight ratios compared with those exposed to RA + hyperoxia. Hyperoxia for 7 days also caused a significant increase in hepatic and pulmonary CYP1A1/1A2 expression compared with air-breathing controls. RA + hyperoxia treatment lowered the expression of these genes. Seven to 30 days after withdrawal of hyperoxia, the animals showed marked induction of hepatic and pulmonary CYP1A1/1A2 expression, but animals that had been given RA + hyperoxia displayed lower expression of these enzymes. On postnatal days 22 or 38, the hyperoxic animals displayed retarded lung alveolarization; however, the RA + hyperoxia-exposed animals showed improved alveolarization. The improved alveolarization in animals given RA + hyperoxia, in conjunction with the attenuation of CYP1A1 and 1A2 expression in these animals, suggests that this phenomenon may play a role in the beneficial effects of RA.