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expert reaction to study looking at exposure to PBDEs in the womb and risk of hypospadias

Researchers publishing in JAMA Pediatrics investigate the association between in utero polybrominated diphenyl ether (PBDE) exposure as measured in maternal hair and increased risk for hypospadias – a congenital condition in males in which the opening of the urethra is on the underside of the penis.

 

Dr Oliver Jones, Associate Professor of Analytical Chemistry, RMIT University, said:

“This is an interesting paper on a topic that I am sure will be of some interest. It is one of a number of recent studies that have found correlations between environmental pollutants and potential endocrine disruption in humans.  Of course, correlation is not causation, and not all studies of this type have found the same results.

“In this case the experiments seem to have been conducted carefully and with considerable thought to the study design. I also think the authors did a thorough job taking cofounding factors into account when analysing the data. One possible limitation is however, that all the patients come from a clinic specializing in hypospadias so the results may not be representative of the general population. The study also used levels of PBDEs in hair in the present as a substitute for the levels of PBDEs that were in the blood during pregnancy in the past. This means we don’t really know what levels the mothers or children were exposed to – or what other factors might be involved. So overall the work is interesting but it is not conclusive.

“It should perhaps also be kept in mind that some of the more common PBDEs were added to the Stockholm Convention (an international treaty to control and phase out major pollutants) in 2017 so levels are likely to decrease, thus limiting potential exposure, in future.”

 

Prof Jean Golding, Emeritus Professor of Paediatric and Perinatal Epidemiology, University of Bristol, said:

“This project is important in addressing the question as to what may be causing the increasing rate of a particular malformation of the penis known as hypospadias. The authors have compared the levels of chemicals that are used in a number of products to reduce the risk of fire. They found increased levels of these chemicals in the hair of women who had recently given birth to children with hypospadias compared with controls.

“There are limitations to the study however. (1) The study relies on a comparison of cases with controls, but the number of controls were much smaller than the number of cases (64 v 152). (2) It is important in case-control comparisons that the controls are chosen from the same population and using the same criteria as the cases, but this was not obviously true as the controls all came from a group of women who were part of a particular programme, but this was not true of the children with hypospadias. They are not therefore ideal controls. (3) This is the first study to address the question as to whether there is a link between these chemicals and hypospadias and, as with all such observational studies, it is important that they be confirmed in other studies before being considered causal. It is an important question as these chemicals are very prevalent in the home environment. If they are doing harm it is important that further research be done into the question.”

 

Prof Sir Colin Berry, Emeritus Professor of Pathology, QMUL, said:

“This appears to be carefully done but there is an amazing leap of faith about its probable significance in relation to causation. The ranges in both controls and “test” subjects are wide (and overlap) and the confidence intervals are very wide.

“No note is made about diet which is often variable in pregnancy – soy proteins have been associated with hypospadias (Golding) on the basis of a more directly obvious prospective mechanism (via oestrogens) than this.”

 

Dr Rod Mitchell, Honorary Consultant Paediatric Endocrinologist at MRC Centre for Reproductive Health, said:

“PBDEs are a group of chemicals used as flame retardants in a variety of products, notably electrical equipment and upholstery. Whilst PBDEs may accumulate in the environment, the majority of PBDEs are no longer used commercially in the UK.

“Hypospadias is an abnormality of the urethra which may occur in association with other male reproductive disorders or as an isolated finding. Hypospadias in males can result from a reduction in testosterone production during fetal life.

“This relatively small study describes an association between hypospadias in boys and the level of PBDEs measured in their mothers. Maternal PBDE levels were higher in boys with hypospadias compared with those without.

“In this study, PBDEs were measured in the hair of the mother 3-18 months after the baby was born. Whether this reflects PBDE levels during pregnancy, when hypospadias occurs, is uncertain. A previous study involving a smaller number of babies found no such association between PBDE and hypospadias when PBDEs were measured in maternal blood during pregnancy.

“In this study, whilst the level of maternal PBDEs was generally higher in the mothers of babies with hypospadias, it is important to note that there was a lot of overlap between the maternal PBDE levels for boys born with or without hypospadias. Therefore, if PBDE exposure can influence the development of hypospadias it is likely to be a small effect impacted by additional genetic or environmental factors.

“Importantly, association does not necessarily mean causation. Demonstrating causation requires laboratory studies to test whether this level of exposure to PBDEs can cause hypospadias, or can lead to alterations in hormones (e.g. testosterone) that are known to result in hypospadias.

“The results of this study do not suggest that changes to current recommendations for pregnant women are required.”

 

Prof Ieuan Hughes, Emeritus Professor of Paediatrics, University of Cambridge, said:

“The design of and interpretation of the results of this study does not make a persuasive argument for PBDEs having a role in its causation of hypospadias.

“Polybrominated diphenyl ethers ( PBDEs) designed as flame retardants have been in the news for some time as examples of chemicals with endocrine-disrupting properties. So now we have a paper which reports an association between exposure to these compounds during pregnancy with an increased risk of hypospadias in male offspring. This condition is present at birth where the opening of the urethra ( the tube from the bladder) is not completely at the tip of the penis. It is quite common, affecting about one in every three hundred boys born. Some, but not all, studies suggest there has been an increase in its prevalence.

“This study used samples of hair cut from the scalps of mothers during their pregnancies and also from the scalp of their babies to measure PBDEs. There was also a control group. The levels were significantly higher in the hair samples of mothers who had boys with hypospadias and even higher in the hair of the affected boys. This group had undertaken the same kind of study in boys with undescended testes with similar findings.

“On first sight, the results are persuasive of adverse effects from PBDEs in the environment on development of the male genitalia before birth. But, hypospadias can be associated with a myriad of other factors not least low birth weight where the association is strong. The authors part compensated for this by more detailed analysis and while there was still an association with PBDEs exposure, the link was weaker. There are also known genetic causes of hypospadias as well as the condition running in families which was not addressed in this study. In discussing why PBDEs may affect male development, the authors refer to how these compounds can interfere with the estrogen ( female hormone) pathway, yet it is androgens ( the male hormone) which are essential for male development during a male programming window in early pregnancy.”

 

* ‘Association of In Utero Exposure to Polybrominated Diphenyl Ethers With the Risk of Hypospadias’ by Shirley Poon et al. published in JAMA Pediatrics on Monday 30 July 2018. 

 

Declared interests

Dr Oliver Jones: “No conflicts of interest to declare.”

Prof Jean Golding: “I have no conflicts of interest.”

Prof Sir Colin Berry: “No conflicts of interest.”

Dr Rod Mitchell: “My research group works on the effects of environmental chemicals and pharmaceuticals on testicular development and male reproductive health. We have no association with the authors and no conflict of interest.”

Prof Ieuan Hughes:  “No conflicts of interest.”

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