PROJECT SUMMARY The economic and public health burden of neurological diseases are remarkably high in Bangladesh with 5,344 cases per 100,000 people. Yet, the etiology of neurological disorders with respect to environmental pollutants, particularly toxic metals such as arsenic (As), lead (Pb), manganese (Mn), and cadmium (Cd), is poorly understood. These metals co-exist at moderate to high levels posing additional risk to children. Recent Bangladesh studies, including our own, have shown neurobehavioral (NB) effects associated with single metal exposure in children living in the rural areas. These detrimental effects, often subtle, potentially have long-term impact on the educational, social, and economic development of the population. This is, in part, due to the limited research capacity of local Bangladeshi researchers to properly evaluate the impact of mixed metal-induced impairment on brain function. To address this fundamental gap in critical research capacity, we plan to improve the research skills of Bangladeshi scientists by providing them the necessary training to appropriately investigate children’s brain vulnerability induced by metal co-exposure. The proposed study has assembled a group of U.S. investigators from Sam Houston State University, Columbia University, the University of Houston, Baylor College of Medicine, and the University of Iowa. The U.S. scientists will collaborate with the Bangladeshi researchers and faculty from the International Center for Diarrheal Disease Research, Bangladesh (icddr,b), Bangabandhu Sheikh Mujib Medical University (BSMMU), the largest medical university in Bangladesh, and North South University (NSU). Our goal is to improve the research capacity of scientists and clinicians by (i) organizing in-country and virtual yearly workshops/training and symposia on neuro-epidemiological research methodology and manuscript preparation; (ii) providing within the U.S. (and virtually), training on various neurobehavioral (NB) evaluation tools and data analysis; and (iii) involving the local researchers in two proposed epidemiological studies to be conducted in Bangladesh. In the first study, 600 adolescents from the Health Effects of Arsenic Longitudinal Study (HEALS) cohort in Araihazar will be evaluated for NB performance. Concurrently, adolescent blood samples will be analyzed for metals and thyroid hormone (TH) since metals are known to disrupt TH prenatally leading to poor NB performance in childhood. Free thyroxine (fT4), total triiodothyronine (tT3), thyroid stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) will be analyzed. The Behavioral Assessment and Research System (BARS) battery will be used for NB assessment. The second study will recruit 200 mother-child pairs from the Health and Demographic Surveillance System (HDSS) area in Matlab to assess if maternal metal mixture exposure is associated with TH disruption in early pregnancy, and in turn, if prenatal disruption of TH interferes with NB performance in young children. Together, these two studies will test if metal- induced neurotoxicity in early life, in part, mediate the relationships between metal co-exposure and NB.

PROJECT NARRATIVE Children in low and middle-income countries (LMIC) are at high risk of neurobehavioral (NB) abnormalities from exposure to toxic metals such as arsenic, lead, manganese, and cadmium, which potentially from their thyroid disrupting properties, are known to impede normal brain development. In Bangladesh, research studies on NB impact of metal co-exposure and the underlying mechanisms are lacking due to inadequate brain research infrastructure. This project aims to improve neuro-epidemiological research capacity of Bangladeshi scientists by providing training on epidemiological, biostatistical, and neurocognitive research methodology both in-country and in the U.S. so that they can apply the skills in examining child development and the potential mechanisms of mixed-metal neurotoxicity.