Boys exposed to a mix of banned chemicals while in the womb have a higher risk of testes birth defects.

Aug 26, 2008

Brucker-Davis F, K Wagner-Mahler, L Delattre B Ducot5, P Ferrari, A Bongain, J-Y Kurzenne, J-C Mas, P Fe´nichel and the Cryptorchidism Study Group from Nice Area. 2008. Cryptorchidism at birth in Nice area (France) is associated with higher prenatal exposure to PCBs and DDE, as assessed by colostrums concentrations. Human Reproduction 23:1708 - 1718.



Synopsis by Jennifer Adibi and Wendy Hessler

 

Using a novel methodology, researchers found a possible link between total chemical contamination in the bodies of pregnant women and the risk of cryptorchidism in their male babies. Fifty seven percent of the mothers whose babies were born with the defect had the highest combined concentration of polychlorinated biphenyls (PCBs) and dichloro-diphenyl-trichloro-ethylene (DDE) in their breast milk, Cryptorchidism is a disorder that occurs when the testes do not descend into the scrotal sac before birth. It is a direct result of low testosterone late in pregnancy and has been increasing in the industrialized world.

Context

Male fertility has declined in Europe during the last two decades (Andersson et al. 2008). Researchers partially suspect that exposure to the staggering number of chemicals in homes and food is related to the decrease. Phthalates and other modern chemicals have been detected in the urine of most U.S. residents in population-wide surveys (CDC 2005). Many of these chemicals, such as those measured in this study, can block the actions of the male hormones necessary for a healthy reproductive system.

PCBs, DDT and other synthetic chemicals with many chlorine atoms are known as persistent organic pollutants (POPs). Of the synthetic chemicals manufactured during the 20th century, the POPs are among the most harmful to human and wildlife health. Reproductive, brain and immune systems can be affected, leading to birth defects, cancer and behavior problems. The chemicals are slow to degrade, lodge in fat and accumulate in predators. POPs continue to pollute people and the environment, even though most of them are no longer used in the US or other industrialized nations.

Phthalates are best known as additives and are used in a large number of consumer products. They make plastics soft and flexible. They extend the life of fragrances. Current uses include IV (intravenous) tubing and other medical products, soft baby toys, fragrances, nail polish and vinyl products in cars and furniture. The European Union has banned their use in vinyl toys but efforts to do so in the US have failed.

Phthalates and some POPs are endocrine disruptors. This means they can influence a hormone's actions and how the messengers are made or destroyed. While phthalates are not thought to act directly through hormone receptors, animal studies show they can lower testosterone levels, which can influence development of reproductive organs that rely on the hormone to develop properly.

One cause of infertility is cryptorchidism, a birth defect where one or both testes fail to descend into the external scrotal sac before birth. Cryptorchidism is seen in about 3% of male full-term births and 30% of premature births. In most cases, the testes descend after birth or the defect is corrected by surgery, giving an overall prevalence of 1% (Virtanen and Toppari 2008).

Cryptorchidism may indicate that something went wrong in the womb with testosterone production and/or hormone signaling, which are both related to sperm production and the risk of testicular cancer later in life. Most of the evidence for this theory on environmental chemicals as a cause comes from tests on laboratory rats and observations in wildlife species. It is not clear if the theory applies to humans given the biologic differences between species.

Few studies have measured and determined reproductive impacts of chemicals in humans. One study found that the risk of undescended testicles was higher in boys whose mother's had the highest amounts of seven different PBDEs in their breast milk (Main et al. 2007). Another U.S. study found an association between a mothers’ exposure to phthalates and increased distance between the anus and the genitalia (Swan et al. 2005). Both studies point to an increasingly common syndrome - called testicular dysgenesis syndrome - by which males are feminized and the reproductive tract does not form properly.

The rise in cryptorchidism could also be influenced by lifestyles, such as diet and lack of physical activity, or possibly to improved diagnostic practices and reporting of cases. Other known risk factors for this defect are low birth weight, premature birth, having other genital abnormalities and season of birth (Virtanen and Toppari 2008).
 

What did they do?

Researchers in the Nice region of France recruited the parents of baby boys born with cryptorchidism in two different hospitals, one in Nice and one in Grasse, during a three-year period. The scientists compared prebirth exposure to chemicals, as measured through their mother's milk, and the risk of undescended testicles. Once a baby was born with the defect, a doctor examined him to standardize the diagnosis and take exact measurements.

They identified 78 babies with the defect and 94 healthy boys who were born on the same date and in the same place with similar characteristics. For their analysis, they had 164 mother/infant pairs. Within 3-5 days of delivery, the researchers collected a sample of colostrum from the mother. Colostrum, otherwise known as the “first milk,” is a form of breast milk that is produced late in pregnancy and immediately after birth before the more creamy milk comes in. It essentially is serving as a proxy for what was circulating in the mom’s body and in her fetus during pregnancy.

The colostrum was analyzed for three different chemical pollutants including seven polychlorinated biphenyls (PCBs), dichloro-diphenyl-trichloro-ethylene (DDE) and dibutyl phthalate (DBP). They also measured these chemicals in umbilical cord blood confirming their transfer across the placenta from the mother to the fetus.

Using statistical methods, the researchers compared the concentrations of the chemicals in colostrum between the healthy boys and the boys with the defect to see if there was a difference. They also employed statistical models to determine the odds of giving birth to a boy with the defect depending on whether his mom had low or medium versus a high chemical load in her milk. In addition to estimating the effects of the single chemicals, they also combined information on the three different chemicals using a scoring system and compared these composite results (DDE + DBP metabolite + the sum of all PCBs) for low, average and heavy exposure. They also compared totals for just the DDE and the PCBs levels.


What did they find?

The moms in the highest exposure group for the PCBs and DDE alone in breast milk had 2-fold greater odds of giving birth to a boy baby with cryptorchidism as compared to moms with low to medium exposure. Similarly when they combined information on PCB and DDE concentrations into a single score, they saw that moms with high exposure to both chemicals had a 3-fold increased odds of giving birth to a boy with the defect. They did not see an increased risk of cryptorchidism associated with higher exposure to DBP.

Even though all subjects in the study had detectable levels of these chemicals in either their blood or breastmilk, they did not find statistically significant associations when they used the individual measurements of the chemicals. This could mean that their statistical methods were not sensitive enough to detect a relationship. It could also mean that these three chemicals are not the culprits but instead indicators of a larger mixture of chemicals that was associated with the risk of cryptorchidism.

Brucker-Davis et al. adjusted their models for other variables that might also be related to the mothers’ exposure and the babies’ health in order to minimize bias. These include variables related to the mother’s health, age, genetic factors and geographic differences between the two cities in Nice, which are 40 miles apart and ethnically different.

Even though DBP did not appear to be associated with an increased risk of cryptorchidism in the population overall, the four boys whose mothers had high exposures to DBP in their jobs were born with the defect. This number is too small to be significant statistically, but it is an interesting observation nonetheless.


What does it mean?

This finding is important in lending weight to the hypothesis that common chemicals found in the bodies of most people are contributing to the increase in testicular defects and the decline in male fertility. Of the three chemical groups examined, PCBs, at low environmental levels but at the highest exposure levels in the children, had the strongest trends with cryptorchidism. DDE showed similar, but not significant, results.

Nice, located in the French Riviera, is known as a tourist attraction and not a region of heavy pollution. The exposures in these subjects were similar to what has been measured in other European populations and might be considered typical. This study is the first to look at the effects of endocrine disrupting chemicals in this particular population.

These findings are especially striking given that PCBs were banned in France in 1987. DDT was banned in 1972, but it is still present in 88% of this study's subjects and also significantly associated with increased odds of having a baby with cryptorchidism. Despite being banned, PCBs and DDE continue to circulate in the environment, accumulate in the food chain and possibly contribute to health problems, such as cancer and the reproductive abnormalities looked at in this study. As consumers on the top of the food chain, human exposure occurs through fatty foods such as meat, fish and dairy products.

In laboratory studies, DBP was highly effective at producing chyptorchidism in rats, yet this study did not find an association. One reason could be because their methods to analyze the chemicals in the milk and blood were not sensitive enough and very low levels were missed. Another reason may be due to incorrect assumptions that were made in the statistical models about the nature of the biologic relationship between the chemicals and the effects. The toxicity of many endocrine disrupting chemicals does not always increase proportionally with increasing exposure. The higher doses may not always lead to more effects. This type of non linear relationship is often called a low-dose effect or a nonmonotonic dose response.

The authors speculate that the chemicals they measured in this study might be correlated with a larger profile of chemicals that are disrupting endocrine function and development. In other words, it is probable that PCBs alone are not responsible for this association but instead a mixture of chemicals is influencing hormones, and thus, development.


Resources

 Andersson AM, N Jorgensen, KM Main, J Toppari, E Rajpert-De Meyts, H Leffers, A Juul, TK Jensen and NE Skakkebaek. 2008. Adverse trends in male reproductive health: we may have reached a crucial 'tipping point.' International Journal of Andrology 2:74-80.

Centers for Disease Control and Prevention. 2005. Third National Report on Human Exposure to Environmental Chemicals. Atlanta (GA).

Main, KM, H Kiviranta, HE Virtanen, E Sundqvist, JT Tuomisto, J Tuomisto, T Vartiainen, NE Skakkebæk and J Toppari. 2007. Flame retardants in placenta and breast milk and cryptorchidism in newborn boys. Environmental Health Perspectives 115:1519-1526.

Swan SH, KM Main, SL Stewart, RL Kruse, AM Calafat, CS Mao, JB Redmon, CL Ternand, S Sullivan, JL Teague and the Study for Future Families Research Team. 2005. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environmental Health Perspectives 113:1056-61.

Virtanen HE and J Toppari. 2008. Epidemiology and pathogenesis of cryptorchidism. Human Reproduction Update 1:49-58.

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