Folic folate deficiency in this population. Dietary folate
Folic Acid Supplementation to alleviate
cognitive deficits in arsenic-exposed adolescents in Bangladesh: Study protocol
Arsenic (As) is
a neurotoxicant that is found naturally occurring in groundwater of various
concentrations around the world. It is estimated that over 200 million people
around the globe are chronically exposed to arsenic-contaminated groundwater,
that exceed the recommended safety standards set by the World Health
Organization of 10 µg/L 1,2. This environmental hazard is
especially endemic to Bangladesh, where arsenic contaminated tube wells affect
the majority of the country 2–5. Outcomes related to chronic
arsenicism are severe and affect multiple bodily systems such as the nervous
system, which manifests as deficits in intellectual functioning, impaired motor
abilities and neurodevelopmental impairments 6. It is considered a major
public health issue due to the broad range of health effects and the magnitude
of people affected worldwide 3.
Exposure to a
neurotoxic metal like arsenic is a leading contributor to cognitive deficits 7. Children may be more at risk
to the adverse effects of a neurotoxic exposure as the nervous system is
continually developing in childhood through adolescence, and during that time
it undergoes a series of critical periods. It is during these critical periods
where environmental hazards may pose a greater risk on neurodevelopmental outcomes
such as intellectual function 8. Hamadani et al. (2011)
demonstrated in a cohort study that the effects of chronic arsenic exposure in
pre-school age children were negatively associated with IQ and verbal
scores. Furthermore, this inverse
association between arsenic and cognitive performance has been supported by a
series of additional cross-sectional studies 9–11.
status can alleviate the harmful health effects of arsenicism 5. There are dietary
interventions that may reduce the adverse effects of arsenic exposure such as
the introduction of a folic acid supplement 1,12. High folate status is an
important contributor to efficiently metabolizing arsenic in the body 1.
Disproportionately large numbers of Bangledeshi
are folate deficient. Bangladesh is uniquely positioned to examine folate
deficiency as staple foods are not fortified with folic acid, as in other parts
of the world, and the nature of their cooking methods destroys the natural
folate found in food13,14. Taken together, these factors
further exacerbates folate deficiency in this population. Dietary folate deficiency is
a problem as research shows that it causes a reduction in urinary arsenic excretion1,15,16. Consequently, Bangladeshi
children are even further vulnerable to the effects of arsenic toxicity due to
the prevalence of malnutrition16.
intake during childhood has been shown to be adversely related to
neurodevelopment yet few researchers have explored the link between folate
supplementation and cognitive performance in arsenic-exposed adolescents17. The value in examining an
older cohort of children than most previous studies, is that the neurodevelopmental
effects associated with arsenic exposure may only be detected much later in
adolescence with intelligence tests2. This suggests that current
tools are not particularly sensitive at capturing cognitive disparities in
young children as of yet, and this older age group has received little
attention in developmental studies2. Other reasons to explore a
diet-related intervention is due to the need for an effective yet simple intervention
for arsenicosis, as traditional medical treatments, known as chelating agents,
have adverse side effects and, it would greatly benefit those arsenic-exposed
individuals of poor socioeconomic status that have a higher likelihood of
exposure and a limited ability to leave their arsenic-contaminated environments
studies have shown an inverse association between arsenic and cognitive
performance, yet relatively few studies have examined the effectiveness of nutritional
interventions in mitigating against arsenic-induced cognitive impairments9,15.There are many gaps in the
literature in respect to the effectiveness of folate in improving cognitive
performance in adolescents that were chronically exposed to arsenic via
drinking water. Additionally, a large proportion of the literature examined exposed-adults
and only limited research studies focused on adolescents. However, there are
studies that have shown a positive association between maternal folate intake
and cognitive performance in very young children and additional studies have demonstrated
a link in folate intake in reducing arsenic levels. However, there is a gap in
studies that specifically examine folate in mitigating cognitive performance in
arsenic-exposed adolescents, over the age of 15 years, in a randomized
The aim of the
study is to determine whether a folic acid supplementation compared with a
placebo will reduce cognitive deficits in chronic arsenic-exposed 15-16 year
olds with folate deficiency in Araihazar, Bangladesh. It is hypothesized that
folic acid supplementation will mitigate impaired intellectual functioning in chronic-exposed
adolescents compared to those control subjects that were given a placebo supplement.
population will be recruited from the Health Effects of Arsenic Longitudinal
Study (HEALS) which prospectively examines the health effects of a relatively
homogenous cohort in terms of sociocultural characteristics and in chronic arsenic
exposure via drinking wells in Araihazar, Bangladesh20. Recruitment of subjects will
be those of 15-16 years of age. Arsenic exposure will be measured by blood and
urine biomarkers and a sample of the family’s tube well water. Cognitive outcomes
will be measured with various neuropsychological tests that assess a range of cognitive
domains including memory, perceptual reasoning, verbal fluency and attention,
including general intelligence21,18. One of these tests is the
Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) which is appropriate
for 6-16 year olds and has been previously adapted for local settings18,20,22. Eligible subjects will be randomly assigned
to either the folic acid supplementation group (400µg/d) or the placebo drug group1. A 400µg dose of folic acid is the
recommended U.S. dietary allowance for people 14 and older12.
1. Gamble M V, Liu X, Slavkovich V, et al.
Folic acid supplementation lowers blood arsenic. Am J Clin Nutr.
2. Tolins M, Ruchirawat M, Landrigan P.
The developmental neurotoxicity of arsenic: Cognitive and behavioral
consequences of early life exposure. Ann Glob Heal. 2014;80(4):303-314.
3. Pratt M, Wadden P, Gulliver W. Arsenic
keratosis in a patient from Newfoundland and Labrador, Canada: Case report and
review. J Cutan Med Surg. 2016;20(1):67-71.
4. Heck JE, Gamble M V., Chen Y, et al.
Consumption of folate-related nutrients and metabolism of arsenic in
Bangladesh. Am J Clin Nutr. 2007;85(5):1367-1374.
5. Sharma A, Flora SJS. Nutritional
management can assist a significant role in alleviation of arsenicosis. J
Trace Elem Med Biol. 2018;45(July 2017):11-20.
6. Naujokas MF, Anderson B, Ahsan H, et
al. The broad scope of health effects from chronic arsenic exposure: Update on
a worldwide public health problem. Environ Health Perspect.
7. Nahar MN, Inaoka T, Fujimura M. A consecutive
study on arsenic exposure and intelligence quotient (IQ) of children in
Bangladesh. Environ Health Prev Med. 2014;19(3):194-199.
8. Nahar MN, Inaoka T, Fujimura M, et al.
Arsenic contamination in groundwater and its effects on adolescent intelligence
and social competence in Bangladesh with special reference to daily
drinking/cooking water intake. Environ Health Prev Med.
9. Wasserman GA, Liu X, LoIacono NJ, et
al. A cross-sectional study of well water arsenic and child IQ in Maine
schoolchildren. Environ Heal A Glob Access Sci Source. 2014;13(1):1-10.
10. Wasserman GA, Liu X, Parvez F, et al.
Water arsenic exposure and intellectual function in 6-year-old children in
Araihazar, Bangladesh. Environ Health Perspect. 2007;115(2):285-289.
11. Von Ehrenstein OS, Poddar S, Yuan Y, et
al. Children’s intellectual function in relation to arsenic exposure. Epidemiology.
12. Peters BA, Hall MN, Liu X, et al. Folic
acid and creatine as therapeutic approaches to lower blood arsenic: A
randomized controlled trial. Environ Health Perspect.
13. Gamble M V., Ahsan H, Liu X, et al.
Folate and cobalamin deficiencies and hyperhomocysteinemia in Bangladesh. Am
J Clin Nutr. 2005;81(6):1372-1377.
14. Watanabe C, Kawata A, Sudo N, et al.
Water intake in an Asian population living in arsenic-contaminated area. Toxicol
Appl Pharmacol. 2004;198(3):272-282. doi:10.1016/j.taap.2003.10.024.
15. Tsuji JS, Garry MR, Perez V, Chang ET.
Low-level arsenic exposure and developmental neurotoxicity in children: A
systematic review and risk assessment. Toxicology. 2015;337:91-107.
16. Hamadani JD, Tofail F, Nermell B, et al.
Critical windows of exposure for arsenic-associated impairment of cognitive
function in pre-school girls and boys: A population-based cohort study. Int
J Epidemiol. 2011;40(6):1593-1604. doi:10.1093/ije/dyr176.
17. Gamble M V., Liu X, Ahsan H, et al.
Folate and arsenic metabolism: A double-blind, placebo-controlled folic
acid-supplementation trial in Bangladesh. Am J Clin Nutr.
18. Veena SR, Krishnaveni G V, Srinivasan K,
et al. Higher Maternal Plasma Folate but Not Vitamin B-12 Concentrations during
Pregnancy Are Associated with Better Cognitive Function Scores in 9- to 10-
Year-Old Children in South India. J Nutr. 2010;140(5):1014-1022.
19. Villamor E, Rifas-Shiman SL, Gillman MW,
Oken E. Maternal intake of methyl-donor nutrients and child cognition at 3
years of age. Paediatr Perinat Epidemiol. 2012;26(4):328-335.
20. Ahsan H, Chen Y, Parvez F, et al. Health
Effects of Arsenic Longitudinal Study (HEALS): Description of a
multidisciplinary epidemiologic investigation. J Expo Sci Environ Epidemiol.
21. Wasserman GA, Liu X, Parvez F, et al.
Arsenic and manganese exposure and children’s intellectual function. Neurotoxicology.
22. Wechsler, D. WISC-IV administration and
scoring manual. San Antonio, TX: Harcourt Assessment; 2003.