Toxoplasma gondii infection/exposure and the risk of brain tumors: A systematic review and meta-analysis

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Introduction

Brain and other central nervous system (CNS) tumors are among the most fatal cancers and cause significant morbidity and mortality in all ages worldwide [1] . These tumors were responsible for 329,673 incident cases, 227,039 deaths and 7.7 million disability-adjusted life-years (DALYs) in 2016 [2] . According to World Health Organization International Classification of Diseases Oncology there are more than 100 histologically distinct subtypes of brain and CNS tumors (referred to as ‘brain tumors’) with different epidemiology, clinical characteristics, treatments, and outcomes [3] . Despite decades of epidemiological and mechanistic studies on the etiology of brain tumors, a few of possible risk factors have been proposed, include: genetic syndromes, exposure to ionizing radiation, cell phone radiation, aspirin use, hormonal factors, pesticides, absence of allergic disorders, dietary factors, and industrial exposures [24] . In past decades, a growing body of studies have investigated the possible roles of infectious agents in the aetio-pathogenesis of brain tumors, and some of these studies demonstrated that individuals infected with some viruses (e.g., cytomegalovirus, simian virus 40, woolly monkey sarcoma virus and human herpesvirus-6 [5] ) might be at higher risk for development of brain tumors, although evidences are insufficient [56] . Moreover, some recent ecological, epidemiological and experimental studies have suggested a possible association between Toxoplasma gondii infection/exposure and increased risk of brain tumors 78910 .

T. gondii is a common neurotropic intracellular protozoan parasite with worldwide distribution [1112] . Based on seroepidemiological estimates, more than one-third of world population are exposed to or latently infected with T. gondii 131415 . This protozoa has a complex life cycle which requires both a definitive host (cat and other felids) and an intermediate host (human or warm-blooded animals) to complete its life cycle [14] . Human infection occurs typically by ingestion of raw or undercooked meat of infected food animals containing tachyzoites or tissue cysts, by oral or accidental ingestion of oocysts existed in the environment (food, vegetables, water or soil), by vertical transmission from mother to foetus, and by blood or organ transplants [1416] . During the chronic stages of infection, T. gondii encysted inside the cells of skeletal, heart, and CNS tissues, leading to lifelong persistence in the hosts [17] . Brain is a preferred site by the parasite to form tissue cysts, and CNS infection by T. gondii may cause immunological and inflammatory responses at the brain tissue that can resulted in neurological and behavioral disorders in both human and animals [18] .

Some epidemiological and clinical evidences suggested the possible role of T. gondii in provoking a subset of brain tumors [81819] . An epidemiological study using data on the national incidence of brain cancers and T. gondii seroprevalence from 37 countries indicated that infection with T. gondii was associated with a 1.8-fold increase in the incidence of brain cancers across the range of T. gondii seroprevalence [20] . Furthermore, another ecological research in France reported that regional mortality rates due to adult brain tumors is significantly correlated with the local seroprevalence of T. gondii [7] . There are also some observational studies evaluating the association between T. gondii infection/exposure and risk of brain tumors, although no study has yet been performed to systematically review and meta-analyze the available data on this topic. Therefore, we designed the present study scrutinizing all existing published studies to critically evaluate whether T. gondii infection/exposure associates with the increased risk of brain tumors, or not.