Original articleZinc and pregnancy: Marked changes on the immune response following zinc therapy for pregnant females challenged with Trypanosoma cruzi
Introduction
During pregnancy, levels of various hormones and serum factors that may modulate lymphocyte or macrophage synthesis, activation, and/or function shift considerably to support a healthy pregnancy.1 This adaptation plays a protective role in the feto-maternal relationship, protecting the fetus from rejection by the maternal immune system while at the same time maintaining adequate maternal host defense mechanisms to fight infection.
A wealth of new information on how the immune system develops and operates has provided new insights into the complex and multifaceted host immune response to Trypanosoma cruzi. Because in vivo models may provide data with clearer clinical relevance, several different experimental models have been used to mimic human infection, including sylvatic rodents,2, 3 mice4 and rats.5, 6
Growing evidence indicates that infectious processes during pregnancy have significant effects on maternal health and can lead to adverse pregnancy outcomes, including spontaneous abortion, pre-term labor, preeclampsia, and intrauterine growth restriction.7 Moreover, emerging evidence supports a bi-directional interaction between nutrition status and incidence of infectious disease, such that the consequences on target tissues of either one are moderated by the other. A functional decline in plasma zinc levels has been reported during the acute phase of infections. This decline is likely due to an increased zinc requirement in the host because pro-inflammatory cytokines mediate changes in hepatic zinc homeostasis, leading to the sequestration of zinc into liver cells and subsequently to hypozincemia.8
Nutritional zinc requirements are difficult to determine because many dietary factors affect the bioavailability of zinc, and physiological requirements of zinc vary greatly between different conditions and age groups. Different intervention trials have been tested and have found that supplementation with daily intakes of 10–30 mg of zinc can be considered an important adjuvant therapy for treating infectious diseases in children in developing countries.9
Physiologically, zinc serum concentrations decline during pregnancy, primarily due to hemodilution and decreased albumin levels.10, 11 While 10.5 mM is considered to be the lower limit of serum zinc during the first and second trimester, zinc levels decline to 9.5 mM in the third trimester.11 Considering that the estimated gestation period in rats is 21 days,12 we hypothesize that zinc levels will sharply decrease during both pregnancy and T. cruzi infection.
Previous studies performed by our group have provided evidence for the involvement of zinc in up-regulating the host's immune response in cases of Chagas' disease, protecting animals against the harmful actions of T. cruzi infection.13, 14 During pregnancy and in cases of T. cruzi infection, nitric oxide (NO) has complex and diverse functions in physiological and pathological events. Among its many biological functions, NO is a potent vasodilator and immune modulator; in addition, NO concentrations are generally elevated during pregnancy.15
NO is a small lipophilic molecule enzymatically originated from cleavage of the terminal guanidino nitrogen of l-arginine by a family of NOS.16 When activated, the NO system triggers enhanced macrophage cytotoxicity, which is the first line of defense against invading pathogens, as it elicits cellular apoptosis in different systems.17
It has been shown by several investigators that IFN-γ, TNF-α, and chemokines are strong inducers of NOS2 and that these molecules are produced in high concentrations during acute T. cruzi infection.18, 19, 20 Conversely, TNF-α and IL-10 negatively regulate NO production.20
As previously described, zinc deficiency leads to impaired function of the specific and non-specific immune response, which can lead to an increased susceptibility to bacterial, viral and parasitic infections.21 Notably, a lack of zinc can impair the development of the immune system, thereby emphasizing the importance of a balanced zinc intake during pregnancy.22 In animals, gestational zinc deficiency induces thymic and splenic involution, consequently impairing active and passive immunity.22
Based on the immunobiology of zinc previously described, our hypothesis was that therapy with this oligoelement can have a protective effect on fetal development and maintenance of the immune response in the infected mother during gestation. To test this hypothesis, we evaluated NO, IFN-γ and TNF-α concentrations and mobilization of peritoneal macrophages during the acute phase of T. cruzi infection.
Section snippets
Pregnancy
Female Wistar rats weighing 180–200 g were used in all experiments. Rats were obtained from the Facility House of the Universitary Campus of Ribeirão Preto. Animals were randomized into the following groups: pregnant control (PC), pregnant control treated with zinc (PCZ), pregnant infected (PI), pregnant infected treated with zinc (PIZ). Each experimental group consisted of 5 animals. The females were housed two to a cage. One male Wistar rat was introduced into each cage and was allowed to
Zinc treatment and its relationship with parameters of fetuses and neonates
The weights and lengths of fetuses (Fig. 1) were significantly higher in infected pregnant rats treated with zinc when compared to PI.
Eighteen days after pregnancy, placental weight from the zinc treated groups was significantly increased compared to controls and infected treated groups; however, there were no differences in placental diameter and in the number of fetuses between the controls and infected treated groups (Fig. 2 and Table 1).
Parasitemia
As shown in Fig. 3, in infected animals, the peak of
Discussion
Zinc has been demonstrated to have a remarkable functional versatility: it is associated with important antioxidant, anti-inflammatory, and anti-apoptotic effects,25 and it has immunoregulator properties in many animal species and humans.
The recommended dietary allowance (RDA) for zinc is 11 mg/day for men and 8 mg/day for women.26 The human body contains 2–3 g zinc, most of which is bound to proteins, with 70% bonded to albumin in circulation. The portal system carries absorbed zinc directly
Statement of authorship
We hereby certify that it is an original publication and the manuscript has not been previously submitted or published elsewhere. CB, CK, LO and AA conceived the study design and conducted the studies. MS performed the histopathological analysis. VB and JP performed the statistical analyses, participated in the study design, and helped in drafting of the manuscript. All authors have made substantial contributions and final approval of the conceptions, drafting, and final version.
Conflict of interest
The authors have no conflicts of interest to declare.
Acknowledgments
We thank Georgius Luiz de Oliveira and Míriam Paula Alonso Toldo of College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo for technical assistance. This study was supported by fellowships from FAPESP.
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