Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants. There are numerous studies reporting developmental cardiac toxicity in multiple fish species due to PAH exposure. However, there are relatively few instances where the effects of acute PAH exposure in adult fish have been characterized. Furthermore, the majority of experiments comparing PAH toxicity with exposure route in adult fish focus on CYP1A gene expression or enzyme activity, while there is a lack of information about the possible pathophysiological effects. Therefore, the overall objective of this thesis was to characterize the sublethal effects of benzo[a]pyrene (BaP), a prototypical PAH, on adult zebrafish (Danio rerio) cardiorespiratory function and fitness following acute exposure by two different routes. In the first experiment, adult zebrafish were intraperitoneally (i.p.) injected twice (one injection/24 hr) with increasing concentrations of BaP (0.1, 10, and 1000 μg/kg) and compared to corresponding dimethylsulfoxide (DMSO) controls. In a second set of experiments, adult zebrafish were aqueously exposed to BaP (static, renewal at 24 hr; 16.2 and 162 μg/L) and compared to DMSO controls. Following 48 hr exposure, one group of fish (n=10/treatment group) were subjected to swimming performance tests to assess critical swimming speed (Ucrit), oxygen consumption rate (MO2), cost of transport (COT), standard metabolic rate (SMR), active metabolic rate (AMR), and factorial aerobic scope (F-AS). Another group of fish (n=12/treatment group) were subjected to echocardiography following 48 hr BaP exposure to evaluate cardiac function. Following echocardiography analysis, samples were collected for parent compound (BaP) body burden and CYP1A mRNA induction analysis. 48 hr BaP injection resulted in significant sublethal effects on adult zebrafish cardiorespiratory function. Oxygen consumption (MO2) was increased at three swimming speeds in injected BaP groups compared to control. In contrast, aqueously BaP-exposed fish showed increased MO2 only at the single lowest swim speed. COT was also similarly increased for both exposure routes. SMR was elevated with both exposure routes, while AMR remained unchanged. This resulted in a significant decrease in F-AS for all treatment groups compared to corresponding controls with both exposure routes. Cardiac function was significantly affected by both routes of BaP exposure. Ventricular heart rate was significantly decreased in BaP-exposed fish, both injected and aqueously-exposed. However, stroke volume was decreased only in fish aqueously exposed to BaP, which resulted in significantly reduced cardiac output with that exposure route. In contrast, the ratio of atrial to ventricular heart rate (AV ratio) was increased only in fish i.p. injected with BaP, indicating the possibility of cardiac arrhythmias occurring. Analysis of BaP body burdens in fish tissue allowed for identification of an overlapping dose group between exposure routes, through which comparisons of cardiotoxicity were then made. This comparison revealed slight differences in cardiotoxicity between exposure routes. BaP-injected fish suffered from more severe bradycardia than aqueously exposed fish. Furthermore, cytochrome P4501A (CYP1A) mRNA levels in liver and heart tissue showed more significant increases in injected fish, while skeletal muscle CYP1A was increased only following aqueous exposure. In conclusion, acute BaP exposure caused metabolic alterations and impaired cardiorespiratory function in adult zebrafish regardless of exposure route. Interestingly, the primary mechanism behind these effects appeared to differ slightly with exposure route. These results suggest that acute BaP exposure may have negative effects on adult fish survivability in the environment. Overall, this work provides valuable insight into the pathophysiogical consequences of acute PAH exposure in adult stage fish.

L’hypothèse prédominante de cette thèse est que les traitements utilisés pour le cancer du sein de stade précoce (chimiothérapie avec des anthracyclines et/ou avec l’anticorps monoclonal trastuzumab) peuvent amener à des toxicités cardiaques à long terme, et qu’une évaluation de ce risque cardiaque ainsi qu’un suivi à long terme sont importants. Pour évaluer la toxicité cardiaque secondaire à ces deux agents chez les patientes avec un cancer du sein de stade précoce, nous avons réalisé deux séries d’études cliniques, la première pour évaluer la toxicité cardiaque à long terme induite par les anthracyclines, et la deuxième pour explorer la toxicité cardiaque induite par le trastuzumab. 1) Le premier chapitre de cette thèse explore la toxicité cardiaque à long terme induite par la chimiothérapie administrée aux patientes avec cancer du sein de stade précoce et ganglions positifs. La population de notre étude a été recrutée au sein de la population d’une étude de phase III randomisée menée entre 1988 et 1996 en Belgique et comparant trois schémas de traitement de chimiothérapie adjuvante, soit deux différents protocoles de chimiothérapies à base d’anthracyclines (basse dose ou haute dose d’epirubicine) ainsi qu’un schéma de chimiothérapie sans anthracyclines (CMF classique). Nous avons identifié 82 patientes (30%) traitées avec chimiothérapie adjuvante dans cette étude qui n’avaient pas de signe de récidive en 2010 (survivantes à long terme). Une évaluation cardiaque approfondie de ces patientes a été effectuée, incluant une échographie cardiaque, une résonance magnétique nucléaire, des marqueurs cardiaques sériques (pro-BNP et troponine), ainsi qu’un test de marche de 6 minutes. Cette étude nous a permis de démontrer que la toxicité cardiaque à long terme liée aux anthracyclines reste faible, et que la résonance magnétique est potentiellement plus précise que l’échographie cardiaque pour mesurer la fonction du ventricule gauche. Ceci devra cependant être confirmé dans d’autres études. Au cours de notre démarche, nous avons été confrontés à la difficulté de motiver les patientes plusieurs années après le traitement pour étudier les potentiels effets à long terme de ce dernier. 2) Le deuxième chapitre de cette thèse explore la toxicité cardiaque induite par l’anticorps monoclonal trastuzumab (anti-HER2). En un premier temps, nous avons examiné la toxicité cardiaque immédiate et à long terme au sein de la population de l’étude HERA, un large essai clinique randomisé de phase III du Breast International Group évaluant le bénéfice du trastuzumab en traitement adjuvant du cancer du sein HER2-positif. Après un suivi moyen de 8 ans des 5,102 participantes de l’étude, nous avons pu démontrer que la toxicité cardiaque demeure faible à long terme, avec très peu de nouveaux évènements cardiaques diagnostiqués dans la phase de suivi. Nous avons aussi pu démontrer que la toxicité cardiaque du trastuzumab apparait surtout pendant la phase de traitement, et qu’une fois le trastuzumab arrêté, la majorité des patientes récupèrent de l’épisode de toxicité cardiaque avec normalisation de la fraction d’éjection ventriculaire gauche. En un deuxième temps, en effectuant une analyse combinée de la toxicité cardiaque dans trois essais cliniques randomisés, nous avons démontré que l’usage concomitant du trastuzumab avec une chimiothérapie néo-adjuvante à base d’anthracyclines augmente le risque d’une toxicité cardiaque chez les patientes ayant un cancer du sein de stade précoce. Conséquemment, ces schémas de traitements ne sont pas recommandés de routine.En conclusion, une bonne évaluation cardiologique et oncologique doit avoir lieu avant de démarrer une chimiothérapie à base d’anthracyclines chez les patientes ayant un cancer du sein de stade précoce. Actuellement, la recommandation est d’évaluer les facteurs de risque cardiaque avant le traitement, et de suivre la fraction d’éjection du ventricule gauche avant, pendant et environs 6 mois après la fin du traitement. L’usage de marqueurs cardiaques et/ou de tests d’imagerie modernes pour un diagnostic de toxicité cardiaque tardive reste un domaine d’investigation intéressant. Pour les patientes avec un cancer du sein HER2-positif de stade précoce, le risque de toxicité cardiaque induite par le trastuzumab demeure faible. Cependant, les facteurs de risque doivent être évalués pour chaque patiente avant le traitement. L‘usage concomitant de trastuzumab et anthracyclines n’est pas recommandé vu le risque augmenté de toxicité cardiaque. En cas de facteurs de risque cardiaque, un dialogue étroit entre l’oncologue et le cardiologue est recommandé avant de débuter un traitement adjuvant. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

Introduction: Some past breast cancer radiotherapy regimens led to an increased risk of death from heart disease. Although heart dose from breast cancer radiotherapy has generally reduced over the past few decades, there may still be some cardiac risk. Estimation of future risk for women irradiated today requires both measurement of their cardiac dose and dose-response relationships, which depend on cardiac dosimetry of past regimens, in conjunction with long-term follow-up data. Methods: Virtual simulation and computed tomography 3-dimensional treatment planning on a representative patient were used to estimate mean heart and coronary artery doses for women irradiated since 1950 in 71 randomised trials in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overview. Patient-to-patient variability in cardiac dose was assessed. Heart and coronary artery doses were also calculated for breast cancer radiotherapy regimens used since the 1950s in Sweden. Cardiac doses from contemporary (year 2006) radiotherapy were assessed for 55 patients who received tangential breast cancer irradiation at a large UK radiotherapy centre. The maximum heart distance (i.e. the maximum distance between the anterior cardiac contour and the posterior tangential field edges) was measured for the left-sided patients, and its value as a predictor of cardiac doses assessed. Results: Mean heart dose for women irradiated in the EBCTCG trials varied from <1 to 18 Gray, and mean coronary artery dose from <1 to 57 Gray. Patient-to-patient variability was moderate. Mean heart dose for women irradiated in Sweden since the 1950s varied from <1 to 24 Gray, and mean coronary artery dose from <1 to 46 Gray. Heart dose from tangential irradiation has reduced over the past four decades. However, mean heart dose for left-sided patients irradiated in 2006 was 2 Gray and around half of them still received >20 Gray to parts of the heart and left anterior descending coronary artery. For these patients, maximum heart distance was a reliable predictor of cardiac doses. For the other patients, mean heart dose varied little and was usually less than 2 Gray. Conclusions: Cardiac doses from breast cancer radiotherapy can be estimated reliably and are now available for use in deriving dose-response relationships in the EBCTCG data and in a Scandinavian case-control study. Cardiac dose has reduced over the past four decades. Therefore the cardiac risk is also likely to have reduced. Nevertheless, for some patients, parts of the heart still receive >20 Gray in the year 2006.

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Evidence that radiation-related cardiovascular disease and second primary cancers can occur in cancer survivors following radiation therapy (RT) has emerged from several independent sources. Cardiotoxicity and second cancers are of particular concern for patients with good prognosis, such as those with Hodgkin lymphoma (HL). HL patients are among the youngest to receive RT, which means that those who are cured of their cancer have decades-long natural life-expectancies during which treatment-related long-term toxicities may cause years of excess morbidity or premature mortality. A considerable amount of research has been conducted to investigate the risk of radiation-related cardiotoxicity and second cancers. However, there are still substantial gaps in knowledge. It is therefore important to improve our understanding regarding these risks and develop treatment approaches and survivorship care to minimise their impact on patients' quality of life. In this thesis, I have investigated the risk of congestive heart failure (CHF) in a cohort of 2619 HL survivors and presented, for the first time, dose-response relationships for risk of CHF versus cardiac radiation doses. I also validated the radiation dosimetry method used to estimate the cardiac doses in this study as well as for other reconstruction methods, versus a gold standard based on the patients' own computed tomography scans. Additionally, I investigated what effect the dose reconstruction errors had on the dose-response relationships. I then focused on modern RT methods and specifically on proton RT. Based on published dose-response relationships (including that developed in this thesis) I predicted cardiovascular and second cancer risks for patients treated with advanced RT. This thesis has provided new knowledge in the study of late effects in HL patients who were treated decades ago as well as for patients treated more recently with advanced RT methods. The results here can be used to facilitate progress towards personalised RT in terms of choosing the appropriate RT method by integrating individualised risk prediction in advanced RT treatment planning. The research here provides the basis for further work towards evidence-based case selection for HL patients for the first NHS proton therapy centres in the UK, opening in 2018-2021.