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Chan, YL, Oliver, BG & Chen, H 2019, 'What lessons have we learnt about the impact of maternal cigarette smoking from animal models?', CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY.View/Download from: UTS OPUS or Publisher's site
Chan, YL, Wang, B, Chen, H, Ho, KF, Cao, J, Hai, G, Jalaludin, B, Herbert, C, Thomas, PS, Saad, S & Oliver, BGG 2019, 'Pulmonary inflammation induced by low-dose particulate matter exposure in mice.', American journal of physiology. Lung cellular and molecular physiology, vol. 317, no. 3, pp. L424-L430.View/Download from: UTS OPUS or Publisher's site
Air pollution is a ubiquitous problem and comprises gaseous and particulate matter (PM). Epidemiological studies have clearly shown that exposure to PM is associated with impaired lung function and the development of lung diseases, such as chronic obstructive pulmonary disease and asthma. To understand the mechanisms involved, animal models are often used. However, the majority of such models represent high levels of exposure and are not representative of the exposure levels in less polluted countries, such as Australia. Therefore, in this study, we aimed to determine whether low dose PM10 exposure has any detrimental effect on the lungs. Mice were intranasally exposed to saline or traffic-related PM10 (1μg or 5μg/day) for 3 wk. Bronchoalveolar lavage (BAL) and lung tissue were analyzed. PM10 at 1 μg did not significantly affect inflammatory and mitochondrial markers. At 5 μg, PM10 exposure increased lymphocytes and macrophages in BAL fluid. Increased NACHT, LRR and PYD domains-containing protein 3 (NLRP3) and IL-1β production occurred following PM10 exposure. PM10 (5 μg) exposure reduced mitochondrial antioxidant manganese superoxide (antioxidant defense system) and mitochondrial fusion marker (OPA-1), while it increased fission marker (Drp-1). Autophagy marker light-chain 3 microtubule-associated protein (LC3)-II and phosphorylated-AMPK were reduced, and apoptosis marker (caspase 3) was increased. No significant change of remodeling markers was observed. In conclusion, a subchronic low-level exposure to PM can have an adverse effect on lung health, which should be taken into consideration for the planning of roads and residential buildings.
Li, G, Chan, YL, Nguyen, LT, Mak, C, Zaky, A, Anwer, AG, Shi, Y, Nguyen, T, Pollock, CA, Oliver, BG, Saad, S & Chen, H 2019, 'Impact of maternal e-cigarette vapor exposure on renal health in the offspring', ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, vol. 1452, no. 1, pp. 65-77.View/Download from: UTS OPUS or Publisher's site
Li, G, Chan, YL, Sukjamnong, S, Anwer, AG, Vindin, H, Padula, M, Zakarya, R, George, J, Oliver, BG, Saad, S & Chen, H 2019, 'A Mitochondrial Specific Antioxidant Reverses Metabolic Dysfunction and Fatty Liver Induced by Maternal Cigarette Smoke in Mice', NUTRIENTS, vol. 11, no. 7.View/Download from: UTS OPUS or Publisher's site
Stangenberg, S, Nguyen, LT, Chan, YL, Zaky, A, Pollock, CA, Chen, H & Saad, S 2019, 'Maternal L-carnitine supplementation ameliorates renal underdevelopment and epigenetic changes in male mice offspring due to maternal smoking.', Clinical and experimental pharmacology & physiology, vol. 46, no. 2, pp. 183-193.View/Download from: UTS OPUS or Publisher's site
OBJECTIVES:Epidemiological and animal studies showed that L-carnitine (LC) supplementation can ameliorate oxidative stress-induced tissues damage. We have previously shown that maternal cigarette smoke exposure (SE) can increase renal oxidative stress in newborn offspring with postnatal kidney underdevelopment and renal dysfunction in adulthood, which were normalised by LC administration in the SE dams during pregnancy. Exposure to an adverse intrauterine environment may lead to alteration in the epigenome, a mechanism by which adverse prenatal conditions increase the susceptibility to chronic disease later in life. The current study aimed to determine whether maternal SE induces epigenetic changes in the offspring's kidney are associated with renal underdevelopment, and the protective effect of maternal LC supplementation. METHOD:Female Balb/c mice (7 weeks) were exposed to cigarette smoke (SE) or air (Sham) for 6 weeks prior to mating, during gestation and lactation. A subgroup of the SE dams received LC via drinking water (SE + LC, 1.5 mmol/L) throughout gestation and lactation. Male offspring were studied at postnatal day (P)1, P20, and 13 weeks. RESULTS:Maternal SE altered the expression of renal development markers glial cell line-derived neurotrophic factor and fibroblast growth factor 2, which were associated with increased renal global DNA methylation and DNA methyltransferase 1 mRNA expression at birth. These disorders were reversed by maternal LC administration. CONCLUSION:The effect of maternal SE on renal underdevelopment involves global epigenetic alterations from birth, which can be prevented by maternal LC supplementation.
Ng, SW, Chan, Y, Chellappan, DK, Madheswaran, T, Zeeshan, F, Chan, YL, Collet, T, Gupta, G, Oliver, BG, Wark, P, Hansbro, N, Hsu, A, Hansbro, PM, Dua, K & Panneerselvam, J 2019, 'Molecular modulators of celastrol as the keystones for its diverse pharmacological activities.', Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, vol. 109, pp. 1785-1792.View/Download from: UTS OPUS or Publisher's site
In the recent years, much attention has been focused on identifying bioactive compounds from medicinal plants that could be employed in therapeutics, which is attributed to their potent pharmacological actions and better toxicological profile. One such example that has come into the light with considerable interest is the pentacyclic triterpenoid, celastrol, which has been found to provide substantial therapeutic properties in a variety of diseases. In an effort to further accelerate its potential to be utilized in clinical practice in the future; along with advancing technologies in the field of drug discovery and development, different researchers have been investigating on the various mechanisms and immunological targets of celastrol that underlie its broad spectrum of pharmacological properties. In this review, we have collated the various research findings related to the molecular modulators responsible for different pharmacological activities shown by celastrol. Our review will be of interest to the herbal, biological, molecular scientist and by providing a quick snapshot about celastrol giving a new direction in the area of herbal drug discovery and development.
Chen, H, Chan, YL, Linnane, C, Mao, Y, Anwer, AG, Sapkota, A, Annissa, TF, Herok, G, Vissel, B, Oliver, BG, Saad, S & Gorrie, CA 2018, 'L-Carnitine and extendin-4 improve outcomes following moderate brain contusion injury.', Scientific reports, vol. 8, no. 1.View/Download from: UTS OPUS or Publisher's site
There is a need for pharmaceutical agents that can reduce neuronal loss and improve functional deficits following traumatic brain injury (TBI). Previous research suggests that oxidative stress and mitochondrial dysfunction play a major role in neuronal damage after TBI. Therefore, this study aimed to investigate two drugs known to have antioxidant effects, L-carnitine and exendin-4, in rats with moderate contusive TBI. L-carnitine (1.5 mM in drinking water) or exendin-4 (15 µg/kg/day, ip) were given immediately after the injury for 2 weeks. Neurological function and brain histology were examined (24 h and 6 weeks post injury). The rats with TBI showed slight sensory, motor and memory functional deficits at 24 h, but recovered by 6 weeks. Both treatments improved sensory and motor functions at 24 h, while only exendin-4 improved memory. Both treatments reduced cortical contusion at 24 h and 6 weeks, however neither affected gliosis and inflammatory cell activation. Oxidative stress was alleviated and mitochondrial reactive oxygen species was reduced by both treatments, however only mitochondrial functional marker protein transporter translocase of outer membrane 20 was increased at 24 h post injury. In conclusion, L-carnitine and exendin-4 treatments immediately after TBI can improve neurological functional outcome and tissue integrity by reducing oxidative stress.
Chen, H, Li, G, Chan, YL, Chapman, DG, Sukjamnong, S, Nguyen, T, Annissa, T, McGrath, KC, Sharma, P & Oliver, BG 2018, 'Maternal E-Cigarette Exposure in Mice Alters DNA Methylation and Lung Cytokine Expression in Offspring.', American Journal of Respiratory Cell and Molecular Biology, vol. 58, no. 3, pp. 366-377.View/Download from: UTS OPUS or Publisher's site
E-cigarette usage is increasing, especially among the young, with both the general population and physicians perceiving them as a safe alternative to tobacco smoking. Worryingly, e-cigarettes are commonly used by pregnant women. As nicotine is known to adversely affect children in utero, we hypothesized that nicotine delivered via e-cigarettes would negatively affect lung development. To test this, we developed a mouse model of maternal e-vapor (nicotine and nicotine-free) exposure and investigated the impact on the growth and lung inflammation in both offspring and mothers. Female Balb/c mice were exposed to e-fluid vapor containing nicotine (18 mg/ml nicotine E-cigarette [E-cig18], equivalent to two cigarettes per treatment, twice daily,) or nicotine free (E-cig0 mg/ml) from 6 weeks before mating until pups weaned. Male offspring were studied at Postnatal Day (P) 1, P20, and at 13 weeks. The mothers were studied when the pups weaned. In the mothers' lungs, e-cigarette exposure with and without nicotine increased the proinflammatory cytokines IL-1β, IL-6, and TNF-α. In adult offspring, TNF-α protein levels were increased in both E-cig18 and E-cig0 groups, whereas IL-1β was suppressed. This was accompanied by global changes in DNA methylation. In this study, we found that e-cigarette exposure during pregnancy adversely affected maternal and offspring lung health. As this occurred with both nicotine-free and nicotine-containing e-vapor, the effects are likely due to by-products of vaporization rather than nicotine.
Saad, S, Al-Odat, I, Chan, YL, McGrath, KC, Pollock, CA, Oliver, BG & Chen, H 2018, 'Maternal L-carnitine supplementation improves glucose and lipid profiles in female offspring of dams exposed to cigarette smoke.', Clinical and experimental pharmacology & physiology, vol. 45, no. 7, pp. 694-703.View/Download from: UTS OPUS or Publisher's site
Sex differences in disease susceptibility due to maternal programming have been reported. We previously observed that maternal smoking induced renal disease and neurological changes are restricted to males, while both male and female offspring develop metabolic disorders. We have also found that maternal L-carnitine supplementation during gestation and lactation can significantly improve glucose intolerance and hyperlipidaemia in male offspring. This study aimed to determine whether such beneficial effects can also occur in female offspring. Balb/c female mice were exposed to cigarette smoke (SE) 6 weeks prior to gestation, during gestation and lactation. A subgroup of the SE dams was given L-carnitine (1.5 mmol/L in drinking water) during gestation and lactation. Female offspring were studied at 20 days (weaning) and 13 weeks (adulthood). Maternal smoking increased liver weight (%) and blood glucose levels at 20 days, as well as glucose intolerance and plasma triglycerides levels at adulthood (P < .05). The hepatic lipid metabolic marker adipose triglyceride lipase was downregulated in the SE offspring at 20 days (P < .05). At 13 weeks, the hepatic pro-inflammatory markers IL-1β and TNF-α mRNA expression were upregulated, while the anti-inflammatory marker IL-10 mRNA expression was downregulated in the SE offspring (P < .05). Liver fibrosis was apparent at 20 days and 13 weeks. Maternal L-carnitine supplementation either normalised or suppressed the detrimental effects induced by maternal smoke exposure (P < .05). We conclude that maternal L-carnitine supplementation improves metabolic parameters in the female offspring of SE dams.
Chen, H, Li, G, Chan, YL, Nguyen, T, van Reyk, D, Saad, S & Oliver, BG 2018, 'Modulation of neural regulators of energy homeostasis, and of inflammation, in the pups of mice exposed to e-cigarettes.', Neuroscience letters, vol. 684, pp. 61-66.View/Download from: UTS OPUS or Publisher's site
BACKGROUND:Maternal smoking can lead to perturbations in central metabolic regulators such as neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) signalling components in offspring. With the growing interest in e-cigarettes as a tobacco replacement, this short report assessed central metabolic regulation in offspring of mouse dams exposed to e-cigarettes. We examined the impact of continuous use of e-cigarettes, and e-cigarette replacement of tobacco cigarettes during pregnancy. Supplementation of an antioxidant l-carnitine was also co-used with tobacco cigarette in the mother to determine whether the impact of maternal tobacco smoking was oxidative stress driven. METHODS:Balb/c mice were exposed to either nicotine-containing (E-cig18) or nicotine-free (E-cig0) e-cigarette aerosols or tobacco smoke (SE) prior to mating and until their pups were weaned. After mating, two SE sub-groups were changed to E-cig18 exposure (Replacement), or supplementation l-carnitine while SE was continued. Male offspring were studied at weaning age. RESULTS:The offspring of E-cig0 dams were the heaviest with the most body fat. Replacing SE with E-cig18 during pregnancy resulted in offspring with significantly less body fat. E-cig0 offspring had significantly increased mRNA expression of brain NPY and iNOS. Maternal SE upregulated mRNA expression of NPY, NPY Y1 receptor, POMC downstream components, and iNOS expression, which were normalised in Replacement offspring, but only partially normalised with maternal L-carnitine supplementation during gestation and lactation. CONCLUSIONS:Maternal exposure to either tobacco and nicotine-free e-cigarettes lead to disturbances in the level of central homeostatic control markers in offspring, suggesting that maternal exposure to e-cigarettes is not without risks.
Sukjamnong, S, Chan, YL, Zakarya, R, Nguyen, LT, Anwer, AG, Zaky, AA, Santiyanont, R, Oliver, BG, Goldys, E, Pollock, CA, Chen, H & Saad, S 2018, 'MitoQ supplementation prevent long-term impact of maternal smoking on renal development, oxidative stress and mitochondrial density in male mice offspring.', Scientific reports, vol. 8, no. 1.View/Download from: UTS OPUS or Publisher's site
To investigate the effect of maternal MitoQ treatment on renal disorders caused by maternal cigarette smoke exposure (SE). We have demonstrated that maternal SE during pregnancy increases the risk of developing chronic kidney disease (CKD) in adult offspring. Mitochondrial oxidative damage contributes to the adverse effects of maternal smoking on renal disorders. MitoQ is a mitochondria-targeted antioxidant that has been shown to protect against oxidative damage-related pathologies in many diseases. Female Balb/c mice (8 weeks) were divided into Sham (exposed to air), SE (exposed to cigarette smoke) and SEMQ (exposed to cigarette smoke with MitoQ supplemented from mating) groups. Kidneys from the mothers were collected when the pups weaned and those from the offspring were collected at 13 weeks. Maternal MitoQ supplementation during gestation and lactation significantly reversed the adverse impact of maternal SE on offspring's body weight, kidney mass and renal pathology. MitoQ administration also significantly reversed the impact of SE on the renal cellular mitochondrial density and renal total reactive oxygen species in both the mothers and their offspring in adulthood. Our results suggested that MitoQ supplementation can mitigate the adverse impact of maternal SE on offspring's renal pathology, renal oxidative stress and mitochondrial density in mice offspring.
Chan, YL, Saad, S, Al-Odat, I, Oliver, BG, Pollock, C, Jones, NM & Chen, H 2017, 'Maternal L-Carnitine Supplementation Improves Brain Health in Offspring from Cigarette Smoke Exposed Mothers.', Frontiers in Molecular Neuroscience, vol. 10, pp. 1-15.View/Download from: UTS OPUS or Publisher's site
Maternal cigarette smoke exposure (SE) causes detrimental changes associated with the development of chronic neurological diseases in the offspring as a result of oxidative mitochondrial damage. Maternal L-Carnitine administration has been shown to reduce renal oxidative stress in SE offspring, but its effect in the brain is unknown. Here, we investigated the effects of maternal L-Carnitine supplementation on brain markers of oxidative stress, autophagy, mitophagy and mitochondrial energy producing oxidative phosphorylation (OXPHOS) complexes in SE offspring. Female Balb/c mice (8 weeks) were exposed to cigarette smoke prior to mating, during gestation and lactation with or without L-Carnitine supplementation (1.5 mM in drinking water). In 1 day old male SE offspring, brain mitochondrial damage was suggested by increased mitochondrial fusion and reduced autophagosome markers; whereas at 13 weeks, enhanced brain cell damage was suggested by reduced fission and autophagosome markers, as well as increased apoptosis and DNA fragmentation markers, which were partially reversed by maternal L-Carnitine supplementation. In female SE offspring, enhanced mitochondrial regeneration was suggested by decreased fission and increased fusion markers at day 1. At 13 weeks, there was an increase in brain energy demand, oxidative stress and mitochondrial turnover, reflected by the protein changes of OXPHOS complex, fission and autophagosome markers, as well as the endogenous antioxidant, which were also partially normalized by maternal L-Carnitine supplementation. However, markers of apoptosis and DNA fragmentation were not significantly changed. Thus L-Carnitine supplementation may benefit the brain health of the offspring from smoking mothers.
Chan, YL, Saad, S, Machaalani, R, Oliver, BG, Vissel, B, Pollock, C, Jones, NM & Chen, H 2017, 'Maternal Cigarette Smoke Exposure Worsens Neurological Outcomes in Adolescent Offspring with Hypoxic-Ischemic Injury.', Frontiers in Molecular Neuroscience, vol. 10, pp. 1-17.View/Download from: UTS OPUS or Publisher's site
Hypoxic-ischemic (HI) encephalopathy occurs in approximately 6 per 1000 term newborns leading to devastating neurological consequences, such as cerebral palsy and seizures. Maternal smoking is one of the prominent risk factors contributing to HI injury. Mitochondrial integrity plays a critical role in neural injury and repair during HI. We previously showed that maternal cigarette smoke exposure (SE) can reduce brain mitochondrial fission and autophagosome markers in male offspring. This was accompanied by increased brain cell apoptosis (active caspase-3) and DNA fragmentation (TUNEL staining). Here, we aimed to investigate whether maternal SE leads to more severe neurological damage after HI brain injury in male offspring. Female BALB/c mice (8 weeks) were exposed to cigarette smoke prior to mating, during gestation, and lactation. At postnatal day 10, half of the pups from each litter underwent left carotid artery occlusion, followed by exposure to 8% oxygen (92% nitrogen). At postnatal day 40-44, maternal SE reduced grip strength in grip traction and foot fault tests, which were also reduced by HI injury to similar levels regardless of the maternal group. Limb coordination was impaired by maternal SE which was not worsened by HI injury. Maternal SE increased anxiety level in the offspring, which was normalized by HI injury. Apoptosis markers were increased in different brain regions by maternal SE, with the cortex having further increased TUNEL by HI injury, along with increased markers of inflammation and mitophagy. We conclude that maternal SE can worsen HI-induced cellular damage in male offspring well into adolescence.
Sukjamnong, S, Chan, YL, Zakarya, R, Saad, S, Sharma, P, Santiyanont, R, Chen, H & Oliver, BG 2017, 'Effect of long-term maternal smoking on the offspring's lung health.', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 313, no. 2, pp. L416-L423.View/Download from: UTS OPUS or Publisher's site
Maternal smoking during pregnancy contributes to long-term health problems in offspring, especially respiratory disorders that can manifest in either childhood or adulthood. Receptors for advanced glycation end products (RAGE) are multiligand receptors abundantly localized in the lung, capable of responding to by-products of reactive oxygen species and proinflammatory responses. RAGE signaling is a key regulator of inflammation in cigarette smoking-related pulmonary diseases. However, the impact of maternal cigarette smoke exposure on lung RAGE signaling in the offspring is unclear. This study aims to investigate the effect of maternal cigarette smoke exposure (SE), as well as mitochondria-targeted antioxidant [mitoquinone mesylate (MitoQ)] treatment, during pregnancy on the RAGE-mediated signaling pathway in the lung of male offspring. Female Balb/c mice (8 wk) were divided into a sham group (exposed to air), an SE group (exposed to cigarette smoke), and an SE + MQ group (exposed to cigarette smoke with MitoQ supplement from mating). The lungs from male offspring were collected at 13 wk. RAGE and its downstream signaling, including nuclear factor-κB and mitogen-activated protein kinase family consisting of extracellular signal-regulated kinase 1, ERK2, c-JUN NH2-terminal kinase (JNK), and phosphorylated JNK, in the lung were significantly increased in the SE offspring. Mitochondrial antioxidant manganese superoxide dismutase was reduced, whereas IL-1β and oxidative stress response nuclear factor (erythroid-derived 2)-like 2 were significantly increased in the SE offspring. Maternal MitoQ treatment normalized RAGE, IL-1β, and Nrf-2 levels in the SE + MQ offspring. Maternal SE increased RAGE and its signaling elements associated with increased oxidative stress and inflammatory cytokines in offspring lungs, whereas maternal MitoQ treatment can partially normalize these changes.
Chen, H, Chan, YL, Nguyen, LT, Mao, Y, de Rosa, A, Beh, IT, Chee, C, Oliver, B, Herok, G, Saad, S & Gorrie, C 2016, 'Moderate traumatic brain injury is linked to acute behaviour deficits and long term mitochondrial alterations', CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, vol. 43, no. 11, pp. 1107-1114.View/Download from: UTS OPUS or Publisher's site
Chan, YL, Saad, S, Al-Odat, I, Zaky, AA, Oliver, B, Pollock, C, Li, W, Jones, NM & Chen, H 2016, 'Impact of maternal cigarette smoke exposure on brain and kidney health outcomes in female offspring.', Clinical and experimental pharmacology & physiology, vol. 43, pp. 1168-1176.View/Download from: UTS OPUS or Publisher's site
Increased oxidative stress in the brain can lead to increased sympathetic tone that may further induce kidney dysfunction. Previously we have shown that maternal cigarette smoke exposure (SE) leads to significantly increased oxidative stress and inflammation in both brain and kidney, as well as reduced brain and kidney mitochondrial activity. This is closely associated with significant kidney underdevelopment and abnormal function in adulthood in the male offspring. This study aimed to investigate the impact of maternal SE on brain and kidney health in the female offspring. In this study, the mouse dams were exposed to 2 cigarettes, twice daily for 6 weeks prior to gestation, during pregnancy and lactation. Brains and kidneys from the female offspring were collected at 20 days (P20) and 13 weeks (W13) and were subject to further analysis. We found that mRNA expression of brain inflammatory markers interleukin-1 receptor and Toll-like receptor 4 were significantly increased in the SE offspring at both P20 and W13. Their brain mitochondrial activity markers were however increased at W13 with increased antioxidant activity. Kidney development and function in the female SE offspring were not different from the control offspring. We concluded that although brain inflammatory markers were upregulated in the SE female offspring, they were protected from some of the indicators of brain oxidative stress, such as endogenous antioxidant and mitochondrial dysfunction, as well as abnormal kidney development and function in adulthood. This article is protected by copyright. All rights reserved.
Chan, YL, Saad, S, Pollock, C, Oliver, B, Al-Odat, I, Zaky, AA, Jones, N & Chen, H 2016, 'Impact of maternal cigarette smoke exposure on brain inflammation and oxidative stress in male mice offspring', SCIENTIFIC REPORTS, vol. 6.View/Download from: UTS OPUS or Publisher's site
Vivekanandarajah, A, Chan, YL, Chen, H & Machaalani, R 2016, 'Prenatal cigarette smoke exposure effects on apoptotic and nicotinic acetylcholine receptor expression in the infant mouse brainstem.', NeuroToxicology, vol. 53, pp. 53-63.View/Download from: UTS OPUS or Publisher's site
Infants exposed to cigarette smoked during pregnancy into infancy have increased respiratory and cardiac abnormalities. Nicotine, the major neurotoxic component of cigarette smoke, induces its actions by binding to nicotinic acetylcholine receptors (nAChR), with one downstream effect being increased apoptosis. Using a pre- into post- natal cigarette smoke exposure mouse model (SE), we studied the immunohistochemical expression of nAChR subunits α2, α3, α4, α5, α7, α9, β1 and β2 and two markers of apoptosis, active caspase-3 and TUNEL, in seven nuclei of the medulla and facial nucleus of the pons in male mice. Pups of dams exposed to two cigarettes (nicotine ≤1.2mg, CO ≤15mg) twice daily for six weeks prior to mating, during gestation and lactation (n=5; SE), were compared to pups exposed to air under the same condition (n=5; SHAM) at P20. Results showed that the hypoglossal nucleus had increased α3, α4, α7, α9, Casp-3 and TUNEL, dorsal motor nucleus of the vagus had increased α3, α5, α7, β1 and Casp-3, nucleus of the solitary tract had increased α3 but decreased α4, α5, β1 and apoptosis, cuneate nucleus had increased α3, β2 and Casp- 3, but decreased α5, nucleus of the spinal trigeminal tract had increased α3, α7, β1, lateral reticular nucleus had decreased β1, inferior olivary nucleus had increased β1 but decreased apoptosis, and the facial had increased α2, α3 and α7. This is the first study to demonstrate that nAChR subunits are affected following pre- into post-natal SE and that they simultaneously coincided with changes in apoptotic expression.
Chan, YL, Saad, S, Simar, D, Oliver, B, McGrath, K, Reyk, DV, Bertrand, PP, Gorrie, C, Pollock, C & Chen, H 2015, 'Short term exendin-4 treatment reduces markers of metabolic disorders in female offspring of obese rat dams', International Journal of Developmental Neuroscience, vol. 46, pp. 67-75.View/Download from: UTS OPUS or Publisher's site
Maternal obesity imposes significant health risks in the offspring including diabetes and dyslipidemia. We previously showed that the hypoglycaemic agent exendin-4 (Ex-4) administered from weaning can reverse the maternal impact of 'transmitted disorders' in such offspring. However daily injection for six-weeks was required and the beneficial effect may lapse upon drug withdrawal. This study aimed to investigate whether short term Ex-4 treatment during suckling period in a rodent model can reverse transmitted metabolic disorders due to maternal obesity.
Maternal obesity was induced in female Sprague Dawley rats by high-fat diet feeding for 6 weeks, throughout gestation and lactation. Female offspring were treated with Ex-4 (5 μg/kg/day) between postnatal day (P) 4 and 14. Female offspring were harvested at weaning (P20). Lipid and glucose metabolic markers were measured in the liver and fat. Appetite regulators were measured in the plasma and hypothalamus.
Maternal obesity significantly increased body weight, fat mass, and liver weight in the offspring. There was an associated inhibition of peroxisomal proliferator activated receptor gamma coactivator 1α (PGC1α), increased fatty acid synthase (FASN) expression in the liver, and reduced adipocyte triglyceride lipase (ATGL) expression. It also increased the plasma gut hormone ghrelin and reduced glucagon-like peptide-1. Ex-4 treatment partially reversed the maternal impact on adiposity and impaired lipid metabolism in the offspring, with increased liver PGC1α and inhibition of FASN mRNA expression. Ex-4 treatment also increased the expression of a novel fat depletion gene a2-zinc-glycoprotein 1 in the fat tissue.
Short term Ex-4 treatment during the suckling period significantly improved the metabolic profile in the offspring from the obese mothers at weaning. Long-term studies are needed to follow such offspring to adulthood to examine the sustained effects of Ex-4 in p...
Nguyen, LT, Stangenberg, S, Chen, H, Al-Odat, I, Chan, YL, Gosnell, ME, Anwer, AG, Goldys, EM, Pollock, CA & Saad, S 2015, 'L-Carnitine reverses maternal cigarette smoke exposure-induced renal oxidative stress and mitochondrial dysfunction in mouse offspring.', American journal of physiology. Renal physiology, vol. 308, no. 7, pp. F689-F696.View/Download from: UTS OPUS or Publisher's site
Maternal smoking is associated with metabolic disorders, renal underdevelopment, and a predisposition to chronic kidney disease in offspring, yet the underlying mechanisms are unclear. By exposing female Balb/c mice to cigarette smoke for 6 wk premating and during gestation and lactation, we showed that maternal smoke exposure induced glucose intolerance, renal underdevelopment, inflammation, and albuminuria in male offspring. This was associated with increased renal oxidative stress and mitochondrial dysfunction at birth and in adulthood. Importantly, we demonstrated that dietary supplementation of l-carnitine, an amino acid shown to increase antioxidant defenses and mitochondrial function in numerous diseases, in smoke-exposed mothers during pregnancy and lactation significantly reversed the detrimental maternal impacts on kidney pathology in these male offspring. It increased SOD2 and glutathione peroxidase 1, reduced ROS accumulation, and normalized levels of mitochondrial preprotein translocases of the outer membrane, and oxidative phosphorylation complexes I-V in the kidneys of mouse progeny after intrauterine cigarette smoke exposure. These findings support the hypothesis that oxidative stress and mitochondrial dysfunction are closely linked to the adverse effects of maternal smoking on male offspring renal pathology. The results of our study suggest that l-carnitine administration in cigarette smoke-exposed mothers mitigates these deleterious renal consequences.
Chen, H, Al-Odat, I, Chan, Y, Amgad, S, Wong, M, Gill, A, Pollock, C & Saad, S 2014, 'The impact of maternal cigarette smoke exposure in a rodent model on renal development in the offspring', PLoS One, vol. 9, no. 7, pp. e103443-e103443.View/Download from: UTS OPUS or Publisher's site
This study aimed to investigate whether maternal cigarette smoke exposure can disrupt fetal kidney development by changing the expression of growth and transcription factors essential for renal development, and thereafter predispose the offspring to chronic kidney disease later in life. Female Balb/c mice (6 weeks) were exposed either to cigarette smoke or air under identical conditions, 6 weeks prior to mating, during gestation and during lactation. Male offspring were sacrificed at three time points, postnatal day (P)1, P20 (weaning age), and 13 weeks (mature age). Blood, urine, and kidneys were collected for analysis. At P1, the developmental genes fibroblast growth factor 2, glial cell-line derived neurotrophic factor and paired box 2 were upregulated at mRNA and protein levels; whilst fibroblast growth factor (FGF) 7 and FGF10 were downregulated. At P20, mRNA expression of FGF2, FGF10 and Wingless-type 4 was upregulated by maternal smoke exposure. These changes were normalised in adulthood. Nephron development was delayed, with fewer nephron numbers from P1 persisted to adulthood; while glomerular volume was increased at P20 but reduced in adulthood. Pro-inflammatory marker monocyte chemoatractant protein 1 (MCP1) was increased in the kidney by maternal smoke exposure. These changes were accompanied by an increased albumin/creatinine ratio in adulthood, suggesting reduced renal dysfunction. In conclusion maternal cigarette smoke exposure prior to and during pregnancy, as well as lactation leads to significant renal underdevelopment and functional abnormalities in adulthood. This study confirms the hypothesis that maternal smoking predisposes offspring to chronic kidney disorders.
Chen, H, Chan, YL, Oliver, B, Pollock, C & Saad, S 2019, 'Maternal smoking and foetal brain outcome: mechanisms and possible solutions' in Preedy, V (ed), The Neuroscience of Nicotine: Mechanisms And Treatment., Academic Press-Elsevier., New York.View/Download from: UTS OPUS
Although it is well known that maternal cigarette smoke exposure (SE) is detrimental to the health of children, more than 20% of women continue to smoke during pregnancy. Children exposed to maternal smoking in utero have changes in their brain structure and size, often accompanied by cognitive defects. This may be due to increased brain oxidative stress and inflammatory response in the neonatal period, leading to neuron damage in adulthood. The mitochondria, a major source of cellular oxidative stress, are particularly vulnerable to the damage caused by the free radicals they produce. Interestingly, the female offspring seem to be protected by such adverse impact of maternal smoking. This chapter will specifically review the changes in brain inflammation and oxidative stress and the mechanism of mitophagy machinery. Potential therapeutic strategies will be suggested to mitigate the impact of maternal smoking.
McAlinden, K, Chan, Y, Kota, A, Chen, H, Oliver, B & Sharma, P 2017, 'Maternal E-cigarette Vaping Enhances Development of Allergic Asthma In the Offspring', American Journal of Respiratory and Critical Care Medicine, American Thoracic Society.View/Download from: UTS OPUS
Rationale: E-cigarettes (eCig) are being considered as an alternative to quit cigarette smoking (CS) while their long-term safety and effect on lung patho-physiology are not known. Maternal eCig-vaping may be considered as a safer CS-replacement during pregnancy. Thus the effect of maternal eCig vaping needs further assessment, particularly the effect this has on offspring and development of allergic asthma later in life. Combining mouse models of maternal vaping and allergic asthma and human airway smooth muscle cells (ASM) in vitro we tested whether maternal eCig vaping enhances features of allergic asthma in the offspring.
Methods: Female BALB/c mice were vaped with either eCig vapour (± nicotine) or CS+eCig (+nicotine) or room air (control group). The eCig vaping was started prior to mating and continued during gestation and lactation while CS-exposure was used prior to mating and replaced with eCig during gestation and mating. The female offspring from these mothers were subjected to an ovalbumin (OVA)-induced allergic asthma model. 24 hours after the last aerosolized OVA or saline challenge, lung function measurements were performed using flexiVent (Scireq, Canada) to increasing concentration of methacholine (MCh). Airway inflammation was assessed by counting total immune cell influx in BAL fluid. Human ASM cells were treated with varying concentrations of eCig liquid condensate and key parameters of mitochondrial function were measured with a Seahorse XF analyzer.
Results: Repeated allergen-exposure induced Th2-driven inflammation in OVA-exposed mice, characterized by massive influx of leukocytes predominantly eosinophils (OVA: 3x105±8.3x104 vs Saline: 1.1x102±1x102) and to some extent neutrophils (OVA: 1.3x104±4.4x103 vs Saline: 1.3x102±1.1x102) into the airways. The effect of allergen on airway eosinophilia was significantly enhanced in the offsprings from eCig OVA (+Nic)-exposed mothers when compared with eCig OVA (-Nic) or CS+eCig animals. OVA-exposed ...