One dioxin exposure in the womb affects female fertility in mice for generations.

Dec 01, 2010

Bruner-Tran, KL and KG Osteen. 2010. Developmental exposure to TCDD reduces fertility and negatively affects pregnancy outcomes across multiple generations. Reproductive Toxicology http://dx.doi.org/10.1016/j.reprotox.2010.10.003




 2010-1130threegenerations
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Females exposed to dioxin while developing in the womb could have difficulty getting pregnant – and so could their daughters and their granddaughters. A study with mice finds the reproductive health effects of dioxin last for generations, reducing fertility and increasing the chances of premature delivery. The results support findings from prior animal and human studies that show dioxin can affect fertility, especially if exposures occur at key times of life. This study further shows subsequent generations are at risk, especially from preterm birth, a growing problem for women around the world. Because humans are regularly exposed to low levels of dioxins, these results suggest the chemical could affect women's fertility – and the fertility of their children and grandchildren. 

 

 

Context

Industrial processes produce many types of unwanted chemical byproducts. One of these is a family of legacy compounds known as dioxins. They can be produced during garbage burning, wood pulp bleaching for paper and chemical production. Volcanoes and forest fires also release dioxins into the air.

The dioxin family comprises a large number and variety of chemicals, with many of them on the "dirty dozen" list of the worst persistent organic pollutants. By far, the most studied – and likely the most toxic – variety is TCDD.

Exposure to high levels of dioxins leads to dioxin poisoning. Skin "chloracne," nausea and even death can result after exposure in the workplace or from industrial accidents.

Large exposures to dioxins occur worldwide. They are documented in factory workers; soldiers and civilians exposed to the defoliant Agent Orange during the Vietnam War; and in people who survive industrial accidents, such as the release of dioxin from a chemical manufacturing plant in Seveso, Italy in 1976. 

A bizarre case involving dioxin occurred in 2004 when the Ukrainian presidential candidate Victor Yushchenko was poisoned with large amounts of TCDD. He developed chloracne and was severely disfigured. Although he survived the assassination attempt, he continues to recover.

Most people, though, are exposed to low levels of dioxins – in the part per trillion (ppt) range – through food and the environment. Dioxin is stored in fat, so it can be transferred through the food chain to people, especially via dairy and meats. Even small amounts can stay in the body for years. Because it can accumulate over time, concentrations in the body typically increase with age.

Even at extremely low doses, dioxins can be dangerous. Dioxins are considered endocrine disruptors, because they can alter hormone levels. They also cause cancer, reproductive and developmental abnormalities, and damage to the skin and liver.

Previous studies show that TCDD can affect ovary development in fish and rodents and skew sex ratios in rats (Miller et al. 2004). Women exposed to high levels of TCDD take longer to get pregnant and are more likely to experience complete infertility (Eskenazi et al. 2010).

Scientists have long suspected that the effects of toxicants could begin before birth and the changes could last for generations. Studies on other endocrine disruptors have shown that some chemicals can have these long-lasting effects.

What did they do?

Scientists examined the effects of TCDD on the fertility of female mice for three generations. Mice were exposed once, twice or three times to 10 micrograms of TCDD per kilogram (or 10 parts per billion). The fertility rates of unexposed animals and their offspring were compared to the TCDD-exposed females and their offspring.

For animals that were exposed once, pregnant females (mothers) were fed the chemical on day 15.5 of pregnancy to expose the fetus. At this time of development, the major organs are formed, but the fetus is still growing.

For animals treated twice, some of the females exposed in the womb (daughters) were also fed TCDD at four weeks old – right before puberty. For animals subjected to three doses, some of the daughters were exposed in the womb, at four weeks old and again at nine weeks of age – right after puberty.

At 10-12 weeks of age, the females exposed in the womb were caged and mated with normal males. If the females became pregnant, some of the pups (granddaughters) were raised and bred with normal males at 10-12 weeks of age. This was repeated for four generations – great granddaughters and great-great-granddaughters.

The effects of viral infections on preterm delivery were also investigated after the mouse colony had an outbreak of a common rodent virus called parvovirus. The researchers noticed the virus did not affect the unexposed females, but the TCDD-exposed females experienced preterm delivery.

To investigate the connection, the researchers treated TCDD-exposed pregnant females with lipopolysaccharide (LPS) – an agent that causes inflammation similar to parvovirus – to determine if LPS caused pregnant females to deliver their pups prematurely.

What did they find?

Bruner-Tran and Osteen show that when a pregnant mouse is exposed to 10 micrograms per kilogram TCDD, her daughters have reduced fertility – as measured by their inability to get pregnant. Her granddaughters and great-granddaughters also suffer the same fate.

A little more than half – 44 percent – of the female mice exposed to TCDD once while in the womb were able to get pregnant. However, they frequently delivered early and many of the pups died soon after. Their offspring had similar conception and early delivery problems.

Only about two-thirds (66 percent) of those exposed twice became pregnant. Of their daughters, only about one-third (29 percent) could conceive. These fertility effects held for three more generations – to the great-great-granddaughters.

Infertility and preterm birth plagued the female grandchildren from both the one and two exposure groups. Importantly, the grandchildren were the first generation not directly exposed to the dioxin, suggesting exposure in prior generations contributes to long-term changes – perhaps epigenetic in nature.

None of the female mice exposed three times – in the womb, at four weeks and again at nine weeks – got pregnant. In contrast, all of the unexposed control mice were able to conceive and delivered normally.

Finally, some of the mice were unintentionally infected with the common rodent virus parvovirus. The virus had little effect on unexposed females. However, preterm delivery occurred in the exposed mice, their daughters and their granddaughters.

Similar results were found when they tested the effects of LPS. If the TCDD-exposed females were pregnant when exposed, they always gave birth prematurely, and their pups died within a day.

What does it mean?

Just one prenatal exposure to dioxin can reduce female fertility for generations to come, causing declines in the ability to get pregnant and increases in preterm births. More than one exposure at important developmental milestones leads to further effects, including complete infertility in some of the mice studied.

The results bolster prior findings by the same research group that show TCDD can decrease fertility in female mice exposed in the womb. The findings also support growing evidence of a link between environmental exposures and preterm birth in people. The findings go a step further by showing that exposure to TCDD during development has lasting and worsening effects well into future generations.

In addition, subsequent exposures were even more harmful to fertility, especially if the exposures occur at key times of development – in the womb, before puberty and after puberty. A second exposure before puberty caused reduced fertility that lasted four generations – to the great-great-granddaughters. Three exposures had extreme effects: the females were not able to get pregnant.

Dioxin exposure also increased hypersensitivity to viruses and other agents that cause inflammation and disease. This was seen in the pregnant females previously exposed to dioxin. They were likely to deliver premature pups that died within a day of birth.

In people, dioxins have been linked to miscarriage in women. High human exposures to the chemicals after industrial accidents have caused other reproductive problems that are well documented.

While this study used high doses that are not relevant to typical human exposures, the results clearly show that single exposures can have serious, detrimental effects that can last for several generations, even when no direct exposure occurred. This is most likely due to changes in the genetics that control when genes are turned off and on. These epigenetic changes can be permanent.

People are routinely exposed to small amounts of dioxins through food and air. The chemicals settle in fatty tissues and can be released throughout life – especially during pregnancy, nursing and weight loss. For women, exposure to TCDD in the womb, at puberty and while pregnant mirror the time-of-life exposures examined in this study.

Could exposure to lower doses – much closer to what most women experience –  also have these long-lasting effects? It remains unknown, but studies have tested whether other endocrine disruptors – chemicals known to alter hormones and their actions – can affect reproduction in successive generations. Several studies report that some – including fungicides and pharmaceuticals, like diethylstilbestrol (DES) – can affect exposed rodents, their children and their grandchildren (Skinner et al. 2010).

Resources

Dioxins and their effects on human health. World Health Organization

Eskenazi, B, P Mocarelli, M Warner, W-Y Chee, PM Gerthoux, S Samuels, LL Needham and DG Patterson, Jr. 2003. Maternal serum dioxin levels and birth outcomes in women of Seveso, Italy. Environmental Health Perspectives 111(7):947-953.

Eskenazi, B, M Warner, AR Marks, S Samuels, L Needham, P Brambilla and P Mocarelli. 2010. Serum dioxin concentrations and time to pregnancy. Epidemiology 21(2):224-231.

Miller, KP, C Borgeesta, C Greenfelda, D Tomica and JA Flaws. 2004.  In utero effects of chemicals on reproductive tissues in females. Toxicology and Applied Pharmacology 198(2):111-131.

Schecter, A, L Birnbaum, JJ Ryan and JD Constable. 2005. Dioxins: an overview. Environmental Research 101(3):419-428.

Skinner, MK, M Manikkama and C Guerrero-Bosagna. 2010. Epigenetic transgenerational actions of environmental factors in disease etiology. Trends in Endocrinology and Metabolism 21(4):214-222.

 

 

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