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Review date: April 2019

Citation: Di Nisio A., Sabovic I., Valente U., et al. Endocrine disruption of androgenic activity by perfluoroalkyl substances: clinical and experimental evidence. J Clin Endocrinol Metab. 104(4):1259-1271

 

Background

It is known that the endocrine (hormone) system is vulnerable to environmental influences. Endocrine disrupting chemicals (EDCs) can alter function(s) of the endocrine system and cause adverse health effects to exposed individuals - and potentially their children and subsequent generations. EDCs are now essentially ubiquitous in our environment, and there is growing concern about the detrimental health effects of these chemicals, for which there is little or no safety data.

Important health lessons have been learned from past toxic level exposures to substances such as lead, polychlorinated biphenyls and diethylstilbestrol. However, it is increasingly apparent that low level chronic exposure to EDCs may be very harmful to endocrine health, including fertility. Perfluoroalkyl substances (commonly known as PFCs) are found in many household items, have been implicated in disrupting endocrine function, accumulate in the environment and can remain in the body for a long time.

 

Aim

To investigate the relationship between PFC exposure and male reproductive health.

 

Methods

A cross-sectional study was conducted between June 2017 and May 2018 within an annual screening protocol study designed to evaluate male reproductive health in high schools in Padova, Italy. Participants were divided by geographical areas known to have different PFC exposure levels into high- and medium- exposed (n = 212) and non-exposed (n = 171; control) groups, and this was confirmed by quantifying PFC concentrations. Outcome measures included anthropometric measurements, testicular ultrasound, semen analysis, and sex hormones. In an effort to elucidate mechanistic information, the authors also performed biochemical studies in established in vitro experimental models.

 

Results

A total of 212 men (mean age 18.7 years) in the exposed group and 171 men (mean age 18.5 years) in the control group were included in the study. The exposed group had significantly decreased anthropometric measurements, including testicular volume (14.7 vs 16.1 mL), penile length (8.6 vs 9.7 cm) and anogenital distance (a marker of fetal testosterone exposure; 4.1 vs 4.5cm). There was also a reduction in sperm quality in the exposed group, in particular these men had fewer sperm with a normal morphology (6.1 vs 7.9%). Samples from a subset of 100 participants (50 from each group) underwent further analyses. Higher concentrations of PFCs in plasma and seminal fluid in the exposed group were confirmed and were significantly correlated with an increase in serum testosterone (19.3 vs 15.4 nmol/L), accompanied by a rise in LH (5.5 vs 4.2 U/L).

At in vitro concentrations similar to those measured in the exposed group, subtypes of PFCs elicited a negative effect on testosterone action at the androgen receptor (AR). Further experiments were conducted on perfluorooctanoic acid (PFOA), the subtype of PFCs present in highest concentration. These demonstrated that PFOA reduced binding of testosterone to AR by ~35% and, in a dose-dependent manner, decreased AR nuclear translocation.

 

Conclusions

Young men with high levels of exposure to a class of EDCs known as PFCs had higher levels of testosterone and a reduction in semen quality, testicular volume, penile length and ano-genital distance. PFCs likely mediate this effect via an antagonistic effect on testosterone binding to the androgen receptor.

 

Points to Note
  1. Semen quality and fertility rates are declining. The reason for this is not well understood but Endocrine Disrupting Chemicals (EDCs) are postulated to play a significant role.
  2. Given the inherent challenges and large number of potential confounders in any study investigating EDCs, the investigators have conducted a useful study which will hopefully be a catalyst for further work in this area.
  3. EDCs other than PFCs were not measured or addressed in this study. In addition, other hormones such as dihydrotestosterone and oestradiol were not measured and may have a role in the findings seen.
  4. The question is raised of the clinical significance of some of the statistically significant findings. However, given there are already significant changes seen in men aged 18 years,  the clinical significance is likely to grow considerably with the passage of time and further long-term follow-up studies would be of interest. It is also recognised that with increasing concentrations of EDCs in our environment, subsequent generations may experience greater effect.
  5. With increased recognition of the role (and harm) of EDCs, and the increase in number of chemicals to which we are chronically exposed, these issues are likely to become increasingly important to consider and study in the field of infertility and andrology, but also in all areas of endocrinology including obesity and malignancy.
  6. Further research is vital and hopefully future research into potentially mitigating factors will also follow. In the meantime, environmental, political, community and personal efforts to decrease exposure to PFC and other EDCs would likely be of benefit.

 

Website: https://www.ncbi.nlm.nih.gov/pubmed/30403786