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Mice exposed to low-level arsenic in utero become obese adults. The control mouse, left, was not exposed to arsenic during embryonic development and is a normal weight. In comparison, mice exposed to arsenic at 10 parts per billion, center, and 42 parts per million, right, are heavier.
The study also determined that arsenic exposed mice entered puberty earlier than control mice.
Image Credit: Photo courtesy of NIEHS

Arsenic in drinking water links early puberty and obesity

Fetal female mice exposed in the womb to low levels of arsenic through drinking water, began puberty early and became obese as adults, according to scientists from the National Institutes of Health. This is significant as the level of 10 parts per billion in the study is the current standard allowed by the U.S. Environmental Protection Agency (EPA).

The study appeared online August 21 in the journal Environmental Health Perspectives. It serves as a starting point for examining whether low-dose arsenic exposure could have similar health outcomes in humans. About 44% of all Americans drink municipal water piped and filtered according to EPA standards from ground water. Well water is are used by more than 13.25 million households across the United States and is not always EPA approved.

Scientists from the National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health, divided pregnant mice into three groups. The control group received no arsenic in its drinking water, while the two experimental groups received either the EPA standard of 10 parts per billion of arsenic or 42.5 parts per million of arsenic, a level known to have detrimental effects in mice. One part per billion is a thousand times smaller than one part per million. The mice were exposed during gestation, between 10 days after fertilization and birth, which corresponds to the middle of the first trimester and birth in humans.

"We unexpectedly found that exposure to arsenic before birth had a profound effect on onset of puberty and incidence of obesity later in life. Although these mice were exposed to arsenic only during fetal life, the impacts lingered through adulthood."

Humphrey Yao PhD, NIEHS reproductive biologist and co-author

The impacts Yao is referring to are obesity and early onset puberty, particularly in female mice. Researchers didn't examine whether males also experienced early onset puberty in this study, but they did confirm that male mice exposed to arsenic in utero also gained weight as they aged. Both the low and high doses of arsenic resulted in weight gain.

According to lead author NIEHS biologist Karina Rodriguez PhD, the research team performed the experiment in three separate groups of mice, each with a control group to compare to the experimental groups, achieving similar results. Rodriguez said although the biological process responsible for these effects remains unknown, her study highlights the need to continue researching long-term impacts of what mothers eat, drink, and breathe during pregnancy on the welfare of their offspring.

"It's very important to study both high doses and low doses. Although the health effects from low doses were not as great as with extremely high doses, the low-dose effects may have been missed if only high doses were studied."

Linda Birnbaum, Ph.D., Director, NIEHS and the National Toxicology Program.

Abstract
Background: Mice exposed to high levels of arsenic in utero are more susceptible to tumors such as hepatic and pulmonary carcinoma when they reach adulthood. However, effects of in utero arsenic exposure on general physiological functions such as reproduction and metabolism remain unclear.

Objectives: We evaluated the effect of in utero exposure to inorganic arsenic at the EPA drinking water standard (10 ppb) and tumor-inducing level (42.5 ppm) on reproductive end points and metabolic parameters when the exposed females reach adulthood.

Methods: Pregnant CD-1 mice were exposed to sodium arsenite (0, 10 ppb, or 42.5 ppm) in drinking water from gestational day 10 to birth, the window of organ formation. At birth, exposed offspring were fostered to unexposed dams. We examined reproductive end points (age at vaginal opening, reproductive hormone levels, estrous cyclicity, and fertility) and metabolic parameters (body weight changes, hormone levels, body fat content, and glucose tolerance) of the exposed females in adulthood.

Results: Arsenic-exposed females (10 ppb and 42.5 ppm) exhibited early onset of vaginal opening. Fertility was not affected when females were exposed to the 10 ppb dose. However, the number of litters per female was decreased in females exposed to 42.5 ppm of arsenic in utero. In both 10 ppb and 42.5 ppm groups, exposed females had significantly higher body weight gain, body fat content, and glucose intolerance.

Conclusion: Our findings reveal unexpected effects that in utero exposure to arsenic at a human relevant low dose and a tumor-inducing level leads to early onset of vaginal opening and obesity in female CD-1 mice.

NIEHS supports research to understand the effects of the environment on human health and is part of NIH. For more information on environmental health topics, visit http://www.niehs.nih.gov. Subscribe to one or more of the NIEHS news lists to stay current on NIEHS news, press releases, grant opportunities, training, events, and publications.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

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Grant Number: 1ZIAES102965

Reference: Rodriguez KF, Ungewitter EK, Crespo-Mejias Y, Liu C, Nicol B, Kissling GE, Yao HH-C. 2015. Effects of in utero exposure to arsenic during the second half of gestation on reproductive end points and metabolic parameters in female CD-1 mice. Environ Health Perspect; doi:10.1289/ehp.1509703 [Online 21 August 2015].

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