Malaria remains a significant global health concern, particularly in sub-Saharan Africa. Indoor residual spraying (IRS) with insecticides, primarily targeting mosquito vectors, is a widely employed malaria control strategy. While effective in reducing malaria transmission, the potential long-term consequences of pesticide exposure on human health, especially in vulnerable populations like pregnant women and infants, remain largely unknown. This study focuses on bendiocarb, a carbamate pesticide commonly used in IRS programs. Carbamates are known to interact with the nervous system and have been implicated in immune system disruption. The lack of comprehensive data on the systemic absorption and immunologic effects of bendiocarb in pregnant women and their offspring necessitates further investigation. This study aims to determine if bendiocarb is systemically absorbed and transplacentally transferred to the fetus, and to comprehensively assess its impact on fetal immune development and subsequent immune responses in infancy, specifically in relation to vaccination. Understanding the potential consequences of bendiocarb exposure on fetal and infant immune systems is crucial for evaluating the overall risk-benefit balance of IRS programs and informing future malaria control strategies.

Previous research has highlighted the potential adverse effects of various pesticides on human health. Studies have shown associations between prenatal exposure to organophosphate pesticides and impaired fetal growth and neurodevelopmental deficits in children. Other studies have linked pesticide exposure to increased susceptibility to infections in infants. While some studies have detected trace levels of carbamate pesticides in pregnant women and their newborns, the biological impact on the fetal immune system has not been comprehensively investigated. The existing literature points to the potential for immune system perturbation by carbamate pesticides, but the specific mechanisms and long-term consequences remain unclear. This lack of information underscores the critical need for this study focusing on bendiocarb and its effects on fetal immune development and vaccination response.

This study employed a prospective cohort design involving 300 HIV-negative pregnant women enrolled in Uganda between 12-20 weeks gestation. Participants were randomized to receive either dihydroartemisinin-piperaquine (DP) or sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria (IPTp). Homes were sprayed with bendiocarb between December 2014 and February 2015. The timing of spraying was recorded for each dwelling. Blood samples were collected from mothers at delivery, and from their infants at 8 weeks of age (prior to repeat spraying). Cord blood samples were also obtained. Plasma bendiocarb levels were measured using a sensitive LC/MS/MS method. Immune cell phenotyping and cytokine profiling were performed using flow cytometry. T cell proliferation was assessed by CFSE dilution following stimulation with *P. falciparum* schizont extract (PfSE). The response to measles vaccination (administered at 9 months of age) was evaluated by measuring anti-measles IgG levels at 1 year of age. Statistical analyses included Wilcoxon rank-sum tests, Wilcoxon sign-rank tests, Spearman's rank correlation, and multivariate linear regression. Data were adjusted for confounding factors such as malaria exposure, maternal chemoprevention regimen, congenital CMV infection, infant sex, maternal gravidity, prematurity, and mode of delivery.

The study found that bendiocarb was detectable at high levels in maternal, cord, and infant plasma, demonstrating systemic absorption and transplacental transfer. Prenatal bendiocarb exposure was associated with several significant changes in the fetal immune system. There was a dose-dependent decrease in regulatory CD4 T cells (Tregs), suggesting a potential impairment in immune regulation. Cord blood showed increased levels of various cytokines and chemokines, indicating an enhanced inflammatory response. In vitro experiments showed that bendiocarb inhibited antigen-driven T cell proliferation. Surprisingly, despite these findings, prenatal bendiocarb exposure was associated with higher post-vaccination measles titers at one year of age, indicating a potentially complex and nuanced impact on immune function.

This study provides compelling evidence that in utero exposure to bendiocarb has significant and previously unrecognized impacts on fetal immune system development and function. The observed decrease in Tregs, coupled with increased inflammatory cytokine production and inhibited antigen-driven proliferation, suggests a shift toward an inflammatory immune profile. The higher measles IgG titers in bendiocarb-exposed infants are paradoxical, possibly indicating compensatory mechanisms or a distinct subset of immune responses affected by bendiocarb. The persistence of these effects through the first year of life highlights the long-term consequences of prenatal pesticide exposure. While the higher measles antibody levels might seem beneficial, the overall shift in immune homeostasis toward inflammation raises concerns about potential long-term health consequences, including increased risk of autoimmune diseases or other immune-mediated conditions. These findings necessitate further research into the mechanisms of action and the potential long-term health consequences of bendiocarb exposure.

This study demonstrates that in utero exposure to bendiocarb, a commonly used pesticide in malaria control programs, has significant and multifaceted effects on the fetal immune system. These effects include altered Treg cell numbers, increased inflammatory cytokines, and impaired antigen-driven proliferation. While higher post-vaccination measles titers were observed, the overall impact on immune homeostasis raises concerns about potential long-term health consequences. The findings highlight the need for further investigation into the long-term health risks associated with prenatal pesticide exposure and for a comprehensive risk-benefit assessment of IRS programs.

The study was conducted in a specific geographical location with a particular malaria prevalence and pesticide usage pattern. The generalizability of findings to other settings may be limited. While the study controlled for various confounding factors, the possibility of residual confounding remains. The study lacked data on breast milk bendiocarb levels and did not assess long-term clinical outcomes in children, hence limiting a conclusive causal interpretation.