Elsevier

NeuroToxicology

Volume 78, May 2020, Pages 177-185
NeuroToxicology

Full Length Article
Interaction of Toxoplasma gondii infection and elevated blood lead levels on children’s neurobehavior

https://doi.org/10.1016/j.neuro.2020.03.010Get rights and content

Highlights

  • Seropositivity for anti-T. gondii IgG may be associated with behavioral problems in children.

  • Children with chronic toxoplasmosis were more likely to exhibit disobedient behavior.

  • An interaction T. gondii seropositivity and elevated BLL increases the likelihood of rule breaking behavior.

Abstract

A chronic infection caused by Toxoplasma gondii was considered asymptomatic in immunologically healthy humans, but results from animal and epidemiological studies led to a reconsideration of this assumption. The objective of this study was to evaluate the seroprevalence of T. gondii infection and its possible effects on the behavior of school-aged children in Bahia, Brazil. Serum anti-body determinations were performed by Enzyme-linked Immunosorbent Assay (ELISA). Blood lead levels (BLL) were measured by graphite furnace atomic absorption spectrometry (GFAAS). The evaluation of a child’s behavior was assessed using the Child Behavior Check List (CBCL). Multivariate models applying logistic regression were used to test the association of chronic T. gondii infection and BLL with behavioral outcomes in children. Seroprevalence for anti-T. gondii IgG antibody was 43.7 % (95 %-CI: 35.8–51.9). Significant associations between chronic T. gondii infection and total behavioral problems (OR = 2.50; 95 %-CI: 1.06–5.88), internalizing spectrum problems (OR = 4.35; 95 %-CI: 1.11–17.14) and rule breaking (OR = 2.61; 95 %-CI: 1.12–6.05) were observed. A possible interaction between toxoplasmosis prevalence and lead exposure was detected. Children with above the median BLL and positive for IgG anti-T. gondii showed a 5.51-fold increase (95 %-CI: 1.75–17.38) in the chance of displaying disobedient behavior. The results suggest that T. gondii infection may be contributing to the high indices of behavioral changes. Moreover, these findings are the first evidence for a possible interaction between chronic T. gondii infection and elevated blood lead levels on children’s neurobehavior.

Introduction

Studies have reported a high prevalence of mental health problems in the Brazilian juvenile population, with behavioral changes being one of the most frequent in children and adolescents (Borsa and Nunes, 2011). A large study of more than 70,000 adolescents in several cities in Brazil revealed a prevalence of common mental disorders of 30.0 % (95 %-CI: 29.2–30.8) (Lopes et al., 2016). Another study in the city of Salvador, State of Bahia, Brazil with children aged 49–72 months found an overall prevalence of 23.5 % for behavior problems (Santos et al., 2016). According to Gray et al. (2004) the expected prevalence of behavioral problems in children is approximately 20 %, showing that, in general, Brazil had indicators much higher than acceptable. Seeking evidence that explains the origin of high rates of behavioral problems is a major challenge given the multifactorial nature of the outcome investigated. There are several reports of association of Toxoplasma gondii (T. gondii) with psychiatric disorders in adults. Toxoplasmosis, an infectious, congenital or acquired disease, is a worldwide zoonosis. Its etiological agent is T. gondii, an intracellular protozoan that was described in Brazil and France at the beginning of the last century (Weiss and Dubey, 2009).

A chronic infection caused by T. gondii had been considered asymptomatic in immunologically healthy humans, but results from animal and epidemiological studies led to a reconsideration of this assumption. Evidence indicates that protozoan may cause permanent behavioral changes in its host, seeking to increase its transmission rate (Webster, 2007). Studies suggest that this parasite influences the behavior of rodents in order to increase their susceptibility to predation; infected animals are more active, which increases the interest of cats by prey (Hay et al., 1984). One of the most significant evidence of behavioral changes caused by T. gondii in rodents is the loss of cat odor aversion, while uninfected mice show a strong repulse to cat odor areas; some infected animals not only display a reduction in aversion to cat smell, but even seem to be attracted to areas with such odors (Webster, 2007). Several mechanisms have been proposed to justify the association between T. gondii infection and behavioral changes in its intermediate hosts. These changes can be explained by a range of indirect and/or direct effects, which may involve the immune response, localization of cysts in the brain tissue, modulation of neurotransmission and epigenetic changes (Webster and Mcconkey, 2010; Vyas, 2015). A recent study using mass spectrometry to investigate changes in the composition of synaptic proteins in a murine model of chronic toxoplasmosis infection demonstrated changes in the composition of synaptic proteins in mice infected, with a downregulation of essential components of glutamatergic neurotransmission. The authors suggested that the synaptic changes detected are a consequence of the distinct neuro-inflammatory environment caused by the parasite (Lang et al., 2018).

Due to the difficulty in detecting parasite cysts in humans except after death, the diagnosis of chronic T. gondii infection is based on serology. In a study with students, Flegr (2013) found associations between seroprevalence for T. gondii and increased risk of car accidents, as well as extroversion and lower awareness (p < 0.03). In another study Hinze-Selch et al. (2010) found an association between T. gondii seroprevalence and frequency of patients with psychiatric disorders. In a case-control study with children and adolescents with and without a diagnosis of depression, it was found a higher seropositivity rate for IgG anti-T. gondii antibodies in the group with depression compared to the healthy group (p = 0.046), in addition, seropositivity was significantly higher in patients with suicidal ideation (p = 0.005) (Sapmaz et al. (2019). A systematic review and meta-analysis showed that latent T. gondii infection is associated with bipolar disorder (OR = 1.26), the authors emphasized that small sample sizes is the major limitation among the studies included in the review (Barros et al., 2017). In a population aging cohort, it was determined whether the time trajectories of multiple cognitive domains are associated with exposure to some infectious agents, the authors concluded that exposure to Human Cytomegalovirus, Herpes Simplex Virus-2 and T. gondii may be associated with cognitive deterioration in older individuals (Nimgaonkar et al., 2016). Other infectious diseases have been described as possible causes of neurological impairments. Brazil has one of the highest rates of neuro-infections in the world (Reimer et al., 2010). There is a long list of infectious agents with reports of psychotic symptoms, the most cited are: Treponema pallidum (bacteria that causes syphilis); Viruses such as Herpes Simplex Virus (HSV-1 and-2) and Human Cytomegalovirus (CMV); Retroviruses as the Human Immunodeficiency Virus (HIV) (Yolken and Torrey, 2008).

Other environmental factors have been described as modifiers of human behavior, like exposure to heavy metals such as lead (Pb), which is a ubiquitous environmental contaminant associated with various neurotoxic effects like cognitive and attention deficits and hyperactive disorder, especially in children (Landrigan et al., 2002; Sanders et al., 2009). In Brazil, the activities that constitute the main sources of exposure to Pb include mining, battery recycling, industrial activities, manufacture of lead-glazed ceramics, and inadequate waste disposal (Paoliello and De Capitani, 2005). Environmental exposure to lower Pb levels has been associated with behavioral deviations in children, as well as being associated with various motor, cognitive and social problems (Skerfving et al., 2015). This metal has a wide range of adverse effects on human health, such as reduced intelligence quotient, increased learning disabilities, behavioral problems and adversely affects cardiovascular functioning and other physiological processes (Reyes, 2015). It is important to consider that in children the impact of environmental exposure to toxic substances is more drastic compared to adults, given the behavioral and physiological differences (Moya et al., 2004). Children’s brain is much more sensitive to environmental chemicals at significantly lower levels than those harmful to adults (Winneke, 2011). Child neurobehavioral development is a product of the dynamic relationship between child characteristics, parenting characteristics, and environmental influences during their growth (Qi and Kaiser, 2003).

Although there are several studies showing an association between T. gondii infection with neuropsychiatric disorders in adults, there are no studies investigating whether behavioral changes in children are associated with this parasite infection. This study sought to investigate the association between the prevalence of anti-T. gondii antibodies occurrence in children living in a municipality of Bahia, Brazil with neurobehavioral changes, taking into account co-exposure to Pb, due to its intense use in the glazing process of pottery utensils in the studied community.

Section snippets

Study design and population

This is a cross-sectional study in which school-aged children of both sexes were evaluated. The general population in Aratuípe, Brazil, was estimated at 9127 inhabitants according to IBGE, 2015. In the age group of 5–14 years, it is estimated that there are 1894 children or adolescent in the whole municipality. From 598 children in the age range of 5.5–14 years attending the selected elementary schools in the municipality, 177 children (29.6 %) were included; however full data on behavior and

Results

Of the 142 children participating in the study, 76 (53.5 %) were female. Children were on average 10.7 ± 2.0 years old. Of the total participants, 74 (52.1 %) resided in the Maragogipinho Village. Most of the children were African-Brazilian (59.1 %) and 28.9 % had no father figure present at home. Most families had a monthly income of up to half a minimum Brazilian wage (43.0 %), while very few families had a family income of more than two minimum wages (1.4 %). Regarding maternal education, 38

Discussion

School-aged children were evaluated to investigate the associations between chronic T. gondii infection with neurobehavioral outcomes. It was observed that the neurobehavioral changes in the studied population may be related to the prevalence of anti-T. gondii IgG antibodies. Moreover, we demonstrated that children presenting latent toxoplasmosis and more exposed to lead, the likelihood of displaying rule breaking behavior was significantly augmented. Therefore, we hypothesize that both

Conclusions

The results presented in this study suggest that chronic toxoplasmosis may be associated with a higher frequency of total behavioral problems, internalizing spectrum problems, and difficulty in obeying the rules in social vulnerable children. The association between chronic toxoplasmosis and behavioral changes was identified, regardless of lead exposure, sex, age, CMV and HSV seropositivity 1/2. In addition, this study provides unprecedented information regarding co-exposure toT. gondii and low

Credit author statement

Funding and Study design: Menezes-Filho, J.A.; Study conception: Lima, F.W.M.; Field works, data collection and processing: Martinez, V.O; Bah, HAF; Rocha, R.B.A.; Carvalho, C.F.; Data Analyses: Martinez, V.O. & Menezes-Filho, J.A.; Carvalho, C.F.; Writing: Martinez, V.O.; Reviewing: Menezes-Filho, J.A.; Lima, F.W.M. & Carvalho, C.F.

Declaration of Competing Interest

The authors declare that there is no conflict of interest.

Acknowledgments

We are thankful to the research grant No. SUS0040/2018 provided by CNPq/FAPESB PPSUS call. Victor Otero Martinez had a scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brazil (CAPES), Finance Code 001. We thank the undergraduate students Ana Laura Santos Anjos, Eduardo Lima Wandega, Elisabete Neves and Nathália Hlavinicka who participated in the data collection and other field works. We are very grateful for the participation of parents and their children of the

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