Spina bifida and other neural tube defects have become fairly rare in the United States, thanks in part to folic acid added to foods and campaigns to get childbearing women to take folic acid. But in Bangladesh, spina bifida is a common occurrence on maternity wards; in fact, it is considered to be epidemic.
“No surveillance is done, so it’s not clear how many cases there are,” says Maitreyi Mazumdar, MD, MPH, a neurologist at Boston Children’s Hospital who conducts environmental health research. “Children may die in delivery, or they may die before seeing a surgeon.”
Although folic acid supplementation isn’t widespread in Bangladesh, Mazumdar thinks there is another factor in play: the country’s ongoing epidemic of arsenic poisoning.
An estimated 70 million people in Bangladesh have been chronically exposed to arsenic in drinking water — the unintended result of public health efforts in the 1970s to reduce disease from fecally contaminated pond water. People were urged to switch to well water, and hundreds of millions of wells were dug. Many of them turned out to have high levels of arsenic.
“In the U.S., 10 micrograms per deciliter is thought to be the threshold for harm from arsenic,” says Mazumdar. “In Bangladesh, they allow as high as 50 micrograms, and we see levels more than 1,000.”
Mazumdar has evidence that arsenic may undo the effects of folic acid supplementation. In a study published last month, she compared 55 Bangladeshi children with neural tube defects (NTDs) and 55 controls and assessed their mothers’ folate status around the time of conception. The higher the arsenic concentration in the water supply, the less folic acid seemed to help; once levels went above 10 micrograms per deciliter, folic acid offered no protection from NTDs.
Now, Mazumdar has a five-year grant from the National Institutes of Environmental Health Sciences to explore the relationship between prenatal arsenic exposure and NTDs. While arsenic has been shown to induce NTDs in several animal models, human studies are hard to do in the U.S. because NTDs are so uncommon.
“At Boston Children’s Hospital, because of folic acid supplementation, we might see 10 new kids with neural tube defects in a year,” says Mazumdar. “In Bangladesh, we found nearly 60 affected children within six months. We can use this tragedy to learn more about NTDs and uncover causative pathways and treatments.”
It’s biologically plausible to think spina bifida and arsenic are related, she says. “Arsenic interferes with folate, which we need for many biological functions, including cell division and making DNA and proteins. When you ingest arsenic, folate helps metabolize it — so our hypothesis is that arsenic uses folate up and makes it unavailable for other functions.”
A paper Mazumdar published last year found that arsenic exposure posed the greatest risk for spina bifida in infants when their mothers had mutations in genes involved in folate metabolism. In addition, Mazumdar and pulmonologist Christopher Hug, MD, PhD, have found that arsenic poisoning causes a cystic fibrosis-like illness that in turn causes diabetes. In expectant mothers, gestational diabetes is known to be associated with NTDs.
Mazumdar and her team will explore all these leads, working with multiple hospitals in Bangladesh that care for children with NTDs and run rural clinics, Specifically, the study will investigate:
- whether arsenic alters mothers’ glucose metabolism in a way that disrupts normal tube closure
- how arsenic interacts with folate metabolically
- how folic acid supplementation affects NTD risk in areas of arsenic contamination
- interactions between arsenic and specific genes, including genes already linked to NTDs and genes involved in glucose and folate metabolism
- epigenetic effects of arsenic on nerve tissue (taken from children having surgery to close their spinal cords)
- whether sweat tests for cystic fibrosis (as well as the CF-like illness caused by arsenic poisoning) could be a biomarker to predict NTD risk.
In addition to the science, the project will seek to ameliorate the problem it’s studying. Mazumdar hopes to form a broad-based team to build new clinics for children with spina bifida, together with Boston Children’s neurosurgeon Benjamin Warf, MD and educate local pediatricians (neurologists are scarce in Bangladesh). The project will also work with organizations to fortify the food supply with folic acid and help communities switch to safer water sources. Finally, the team will hold events to raise community awareness of folic acid and NTDs. “There’s a lot of stigma around neural tube defects,” Mazumdar says.
To inquire about supporting or collaborating on this project, email Mazumdar.