How a pregnant woman metabolizes arsenic may be affected by the sex of her fetus, and a male child may be at increased risk for adverse health outcomes. These and other findings were presented Aug. 8 by Elizabeth Martin, Ph.D., at the annual NIEHS Karen Wetterhahn Memorial Award lecture. Martin is a postdoctoral fellow at the University of North Carolina at Chapel Hill (UNC).
“Dr. Martin’s work is providing novel insight into sex-dependent difference following prenatal exposures to arsenic,” said NIEHS Superfund Research Program (SRP) Director Bill Suk, Ph.D., who introduced Martin. “This important work helps us understand underlying interindividual differences and how they relate to disease risk.”
The SRP selected Martin for the 2016 Wetterhahn award for her cutting-edge research on how exposure to arsenic may lead to epigenetic changes. Epigenetic changes affect the function of DNA without altering its original sequence of amino acids. Under the guidance of UNC Superfund Research Center Director Rebecca Fry, Ph.D., Martin studies the relationship among infant sex, epigenetic changes, and birth outcomes in response to prenatal arsenic exposure.
Arsenic metabolites differ
In a group of pregnant mothers, the team measured two types of arsenic metabolites in urine, monomethyl-arsenic (MMAs) and dimethyl-arsenic. They found that higher proportions of MMAs were more prevalent in women carrying male infants. A previous study in Fry’s lab linked higher proportions of MMAs to decreased birth weight in infants. Other studies found links with skin lesions, bladder cancer, and atherosclerosis.
Next, the researchers looked at different forms of arsenic-3-methyltranferase (AS3MT). This enzyme affects arsenic metabolism, and its form can vary among people. Sex-linked differences were discovered.
In mothers pregnant with male infants, Martin and the team discovered a relationship between certain forms of AS3MT and higher urinary concentrations of arsenic metabolites. This group also displayed a relationship between the type of AS3MT and the length of pregnancy. Neither finding was observed in mothers pregnant with female infants.
Martin said that different forms of AS3MT have been linked to adverse health effects in adults. She and other researchers are intrigued by the clues that the form of AS3MT and the sex of a pregnant woman’s baby interact to affect arsenic metabolism. Learning more about that interaction may shed light on who may be at greatest risk from arsenic exposure.
Epigenetics may hold the answer
Examining placentas of mothers carrying male and female infants, the scientists identified 582 genes that were methylated differently in males and females. With links to immune function, transcription factors, and transport proteins, these genes could affect responses to arsenic.
“We saw differences in maternal arsenic metabolism, gene expression, and fetal birth outcomes based on infant sex,” said Martin. “Pre-existing methylation differences in key genes in males and females could lead to subsequent genomic and epigenomic differences, which may result in differential disease susceptibility.”
The Fry Lab is currently assessing sex-specific epigenetic alterations associated with exposure to arsenic and other environmental contaminants.
Drobna Z, Martin E, Kim KS, Smeester L, Bommarito P, Rubio-Andrade M, Garcia-Vargas GG, Styblo M, Zou F, Fry RC. 2016. Analysis of maternal polymorphisms in arsenic (plus3 oxidation state)-methyltransferase AS3MT and fetal sex in relation to arsenic metabolism and infant birth outcomes: Implications for risk analysis. Reprod Toxicol 61:28–38.
Laine JE, Bailey KA, Rubio-Andrade M, Olshan AF, Smeester L, Drobna Z, Herring AH, Styblo M, Garcia-Vargas GG, Fry RC. 2015. Maternal arsenic exposure, arsenic methylation efficiency, and birth outcomes in the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort in Mexico. Environ Health Perspect 123(2):186–192.
Martin E, Smeester L, Bommarito PA, Grace MR, Boggess K, Kuban K, Karagas MR, Marsit CJ, O'Shea TM, Fry RC. 2017. Sexual epigenetic dimorphism in the human placenta: implications for susceptibility during the prenatal period. Epigenomics 9(3):267–278.
(Sara Amolegbe is a research and communication specialist for MDB Inc., a contractor for the NIEHS Division of Extramural Research and Training.)