Mice moms, sons end up diabetic after short BPA exposure during pregnancy.

Mice moms, sons end up diabetic after short BPA exposure during pregnancy.

Jul 01, 2010

Alonso-Magdalena, P, E Vieira, S Soriano, L Menes, D Burks, I Quesada and A Nadal. Bisphenol-A exposure during pregnancy disrupts glucose homeostasis in mothers and adult male offspring. Environmental Health Perspectives http://dx.doi.org/10.1289/ehp.1001993.


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Brief exposure to low levels of bisphenol A during pregnancy may contribute to diabetic symptoms in the mother and her sons – but not daughters – finds a study with mice. BPA, which acts like estrogen and can interfere with normal hormone activity, caused changes in the mothers that resembled gestational diabetes. The mothers gained weight and could not properly regulate insulin, sugars and fats, even four months after the pregnancy. Their male pups showed similar deficits in metabolism, even though they had only been indirectly exposed for a brief period as fetuses.

Context

Intricate body systems process and store energy from food. When needed, sugars and fats are released. These mechanisms are delicately balanced. When they go awry, metabolic problems such as diabetes and obesity can occur. At no time are these systems more vulnerable than during pregnancy, when the energetic demands of the fetus compete with the mother’s regulation of her own body (Haig 1993).

Normally, insulin release causes sugars to be stored in cells for later use. During pregnancy, the body becomes increasingly resistant to insulin. This ensures that enough sugar remains in circulation to feed the growing fetus. Typically, the mother compensates by secreting more insulin so that blood sugar levels are kept in check.

These check and balance systems are easily derailed. When the mother’s body fails to adjust its insulin release, gestational diabetes – which afflicts up to 10 percent of pregnant women – may occur. Most cases of gestational diabetes resolve soon after birth, but many serious consequences may remain for both the mother and child. The children are often dangerously large at birth, and both mothers and offspring may find themselves at increased risk of obesity and Type II diabetes.

Because estrogen may play an important role in regulating the normal changes in metabolism during pregnancy (Nadal et al. 2009), anything that disrupts the body’s normal estrogenic activity may also throw the blood sugar regulation systems into upheaval, causing metabolic symptoms, and possibly contributing to diabetes or obesity.

The environmental chemical bisphenol A (BPA) – found in products throughout the modern world – is a compound that mimics natural estrogens. Concern first surfaced because it can leach from widely-used polycarbonate plastics, which were used a food packaging and water bottles. Recently, several reports brought attention to its overwhelming prevalence in canned goods (Consumer Reports 2009National Workgroup for Safe Markets 2010).

From food to household electronics to sales receipts, BPA is so commonly used in consumer goods that 95 percent of Americans have measureable levels in their blood. During pregnancy, BPA can pass from mother to the developing fetus.

Alarm bells were first raised about the chemical’s safety when animal studies showed that BPA could affect development of the reproductive system and the brain. More recently, concern has turned to whether BPA exposure may also impact metabolism. Several recent studies have linked BPA to diabetes, obesity and other symptoms of impaired metabolism in humans (Lang et al. 2008) and animal models (Alonso-Magdalena et al. 2006).

What did they do?

The researchers examined whether there were long-term metabolic effects on the mother and her pups exposed to BPA for a week during pregnancy.

Researchers injected pregnant mice with BPA from days 9 to 16 of pregnancy, which roughly corresponds to the development stage of middle to late pregnancy in humans. Some of the injected mice received a low dose of 10 micrograms per kilogram (μg/kg) of BPA each day while others received a high-dose of 100 μg/kg each day. Currently, the U.S. Environmental Protection Agency (EPA) and the Food and Drug Administration (FDA) consider anything below 50 μg/kg per day to be a low, and thus, “safe” dose.

The researchers measured glucose in the blood to determine if the pregnant mice processed sugars and responded to insulin – a hormone that helps the body store sugars after a meal. After birth, they continued to monitor the mothers and their offspring for their ability to metabolize sugar and insulin. They also examined how well the animals processed fats and how well their pancreases worked. The researchers compared these measures from BPA-treated mice to untreated mice and determined the physiological differences between the two groups.

What did they find?

Pregnancy typically entails some degree of insulin resistance, and this effect was amplified in the BPA-exposed mice, particularly in those receiving the lower dose of BPA. When compared to the untreated pregnant mice, their cells were less able to efficiently process and store sugars and their liver and muscle tissues showed a reduced insulin response similar to that seen in diabetic conditions.

Four months after giving birth, the BPA-treated mothers were heavier than the controls, even though their diets were the same. The mice in the high-dose group – but not the low-dose groups – had clear deficits in their cells’ ability to use insulin to store sugars. In both BPA-treated groups, levels of triglycerides – a type of lipid or fat – in the blood were elevated.

The mouse pups born to BPA-treated mothers also showed differences from control mouse pups. The low-dose pups were heavier at birth than controls – as is frequently the case with babies born to mothers with gestational diabetes. Yet, the high-dose pups actually weighed less than the controls.

As they aged, the BPA groups showed similar metabolic problems to their mothers. Although no significant differences were seen at three months of age, by six months, male – but not female – offspring in both BPA groups showed clear abnormalities in their ability to use insulin to store sugars. This deficit was consistently apparent in the blood tests and when the pancreatic cells were examined.

What does it mean?

Exposure to low levels of BPA at a crtical time in pregnancy may influence metabolic function during and after pregnancy, setting the stage for long-term gestational diabetes in the mothers and development of diabetes in sons as they age.

This study adds to a growing body of research evidence that, when taken together, suggests BPA causes health problems in animals and quite possibly in humans. Much of the research has focused on reproductive and developmental risks.

This study is one of a number of recent ones investigating whether BPA might have effects on metabolic conditions such as diabetes and obesity. But, it is the first to examine the mother’s risk of developing diabetes during pregnancy. While the recent studies have found some conflicting results, this new study’s methodological strengths mke the findings of particular concern.

Earlier this year, another group of researchers reported that prenatal and early postnatal BPA exposure in mice did not appear to lead to problems with blood sugar regulation, although they did find faster rates of growth during early development (Ryan et al. 2010).The new study improves upon earlier work, however, in that it is particularly comprehensive in its methods and approaches problems of insulin resistance and blood sugar regulation using a number of different methods. From sugar metabolism tests to measures of gene expression to blood chemistry, the multiple lines of evidence in this study all point to BPA having profound negative effects on the body’s ability to properly control blood sugar.

Beyond its methodological strengths, this new study adds two important nuances to our understanding of how BPA may impact metabolism. First, the study showed that even if BPA exposure occurs during a very brief period, the disruption in blood sugar regulation can be long-lasting. The female mice received BPA for only a seven day window during pregnancy, and yet were affected even months later, with higher weights and abnormal blood sugar and lipid levels.

In humans, of course, we are exposed continuously throughout our lifetimes as we ingest BPA in our food and pick it up through plastics and other sources every day. How this constant exposure might affect our bodies’ abilities to regulate blood sugars and other body systems remains an open ended question. However, these early results in mice are enough to merit additional research.

Second, the new study shows intergenerational effects. Males who were exposed to BPA as fetuses through their mothers displayed long-term metabolic problems resembling diabetes, even though they were never exposed to the chemical after birth. Because the body’s systems develop very early in life – often before birth – early exposures can cause permanent changes in body functions. In this case, through the ability to act as a pseudo-estrogen, BPA seems to permanently “program” body responses to sugar, causing an inability in the mice process the sugar – a condition that may mirror some of the most troubling current human health problems.

Aspects of the findings are also puzzling. Surprisingly, only male offspring were affected in this way by BPA exposure. The researchers hypothesize that perhaps the female offspring’s own estrogen production protected against the dysregulation, but further investigation would be needed to address that question.

In addition, low and high-dose BPA exposures didn’t yield the same findings. While both levels of exposure clearly produced negative health effects, it remains uncertain why the mice might respond differently to the two doses. The lower dose more closely approximates average human exposure levels. Ideally, future experiments will need to simulate the typical method of human exposure – ingestion through food – rather than injection.

Still, many questions remain unanswered, and more research is needed to fully understand how BPA impacts regulatory systems.

Resources

Alonso-Magdalena, P, S Morimoto, C Ripoll, E Fuentes and A Nadal. 2006. The estrogenic effect of bisphenol A disrupts pancreatic beta-cell function in vivo and induces insulin resistance. Environmental Health Perspectives 114(1):106-12.

Calafat, AM, Z Kuklenyik, JA Reidy, SP Caudill, J Ekong and LL Needham. 2005. Urinary concentrations of Bisphenol A and 4-Nonylphenol in a human reference population. Environmental Health Perspectives 113:391-5.

Concern over canned foods. 2009. Consumer Reports, December.

Haig, D. 1993. Genetic conflicts in human pregnancy. Quarterly Review of Biology 68(4):495-532.

Lang, IA, TS Galloway, A Scarlett, WE Henley, M Depledge, RB Wallace and D Melzer. 2008. Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. Journal of the American Medical Association 300(11):1303-10.

Nadal, A, P Alonso-Magdalena, S Soriano, AP Ropero and I Quesada. 2009. The role of oestrogens in the adaptation of islets to insulin resistance. Journal of Physiology 587(Pt 21):5031-7.

National Workgroup for Markets. 2010. Silver lining: An investigation into bisphenol A in canned foods (PDF).

Ryan, KK, AM Haller, JE Sorrell, SC  Woods, RJ Jandacek and RJ Seeley. 2010. Perinatal exposure to Bisphenol-A and the development of the metabolic syndrome in CD-1 mice. Endocrinology 151(6):2603-12.