It is predicted that Japan and European Union will soon experience appreciable decreases in their populations due to persistently low total fertility rates (TFR) below replacement level (2.1 child ...per woman). In the United States, where TFR has also declined, there are ethnic differences. Caucasians have rates below replacement, while TFRs among African-Americans and Hispanics are higher. We review possible links between TFR and trends in a range of male reproductive problems, including testicular cancer, disorders of sex development, cryptorchidism, hypospadias, low testosterone levels, poor semen quality, childlessness, changed sex ratio, and increasing demand for assisted reproductive techniques. We present evidence that several adult male reproductive problems arise in utero and are signs of testicular dysgenesis syndrome (TDS). Although TDS might result from genetic mutations, recent evidence suggests that it most often is related to environmental exposures of the fetal testis. However, environmental factors can also affect the adult endocrine system. Based on our review of genetic and environmental factors, we conclude that environmental exposures arising from modern lifestyle, rather than genetics, are the most important factors in the observed trends. These environmental factors might act either directly or via epigenetic mechanisms. In the latter case, the effects of exposures might have an impact for several generations post-exposure. In conclusion, there is an urgent need to prioritize research in reproductive physiology and pathophysiology, particularly in highly industrialized countries facing decreasing populations. We highlight a number of topics that need attention by researchers in human physiology, pathophysiology, environmental health sciences, and demography.
A total of 1,215 young Danish men aged 18-28 years were recruited between 2008 and 2012 when they attended a compulsory medical examination to determine their fitness for military service. The ...participants delivered a semen sample, had a blood sample drawn, and underwent a physical examination. They responded to questionnaires including information on marijuana and recreational drug use during the past 3 months (no use, use once per week or less, or use more than once per week). A total of 45% had smoked marijuana within the last 3 months. Regular marijuana smoking more than once per week was associated with a 28% (95% confidence interval (CI): -48, -1) lower sperm concentration and a 29% (95% CI: -46, -1) lower total sperm count after adjustment for confounders. The combined use of marijuana more than once per week and other recreational drugs reduced the sperm concentration by 52% (95% CI: -68, -27) and total sperm count by 55% (95% CI: -71, -31). Marijuana smokers had higher levels of testosterone within the same range as cigarette smokers. Our findings are of public interest as marijuana use is common and may be contributing to recent reports of poor semen quality.
During the past two decades human exposure to bisphenol A (BPA) and phthalates such as di-iso-butyl phthalate (DiBP), di-n-butyl phthalate (DnBP), butylbenzyl phthalate (BBzP) and di-(2-ethyl-hexyl) ...phthalate (DEHP) has received substantial interest due to widespread population exposures and potential endocrine disrupting effects. Therefore, these chemicals have gradually been restricted and phased out through legislation. However, humans are still exposed to a wide range of other less studied phthalates, phthalate substitutes and BPA analogues as well as other polychlorinated and phenolic substances.
In this study, we investigated human exposure to these chemicals over the past decade. Three hundred urine samples collected in 2009, 2013 and 2017 (100 samples each year) from young Danish men of the general population, participating in a large on-going cross-sectional study, were selected for the present time trend study. The urinary concentration of metabolites of 15 phthalates, di-2-ethylhexyl terephthalate (DEHTP) and di-iso-nonyl-cyclohexane-1,2-dicarboxylate (DINCH), seven bisphenols including BPA, bisphenol S (BPS) and bisphenol F (BPF), as well as triclosan, triclocarban, benzophenone-3, three chlorophenols and two phenylphenols were analyzed by two new sensitive LC-MS/MS methods developed and validated for the present study.
A significant decrease in urinary concentrations over time was observed for the majority of the chemicals. Median concentrations of BPA and the metabolites of DiBP, DnBP, BBzP and DEHP were more than halved from 2009 to 2017. Similar decreases were observed for triclosan and the chloro- and phenylphenols. In contrast, metabolites of the two phthalate substitutes DEHTP and DINCH increased more than 20 and 2 times, respectively. The potential BPA substitutes; BPS and BPF also increased, but only slightly. Despite these new exposure patterns, the exposure to the old well-known chemicals, such as DiBP, DnBP, BBzP, DEHP and BPA was still higher in 2017 compared to the exposure level of the new substitutes such as DEHTP, DINCH, BPS and BPF.
A significant decrease in internal exposure to most of the common phthalates and BPA over the past decade was observed, reflecting market changes and regulatory measures implemented in EU. Despite increasing exposures to some of the known phthalate substitutes and BPA analogues, the total amount of each measured chemical group (original and substitute analytes combined) was lower in the more recently collected samples. This indicates only partial direct substitution or substitution by chemicals not covered in this approach, or a general decline in the exposure to these chemical/product groups over the last decade.
Background: Perfluoroalkyl acids (PEAAs) are found globally in wildlife and humans and are suspected to act as endocrine disruptors. There are no previous reports of PFAA levels in adult men from ...Denmark or of a possible association between semen quality and PFAA exposure. Objectives: We investigated possible associations between PFAAs and testcular function. We hypothesized that higher PFAA levels would be associated with lower semen quality and lower testosterone levels. Methods: We analyzed serum samples for levels of 10 different PFAAs and reproductive hormones and assessed semen quality in 105 Danish men from the general population (median age, 19 years). Results: Considerable levels of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorohexane sulfonic acid were found in all young men (medians of 24.5, 4.9, and 6.6 ng/mL, respectively). Men with high combined levels of PFOS and PFOA had a median of 6.2 million normal spermatozoa in their ejaculate in contrast to 15.5 million among men with low PFOS-PFOA (p = 0.030). In addition, we found nonsignificant trends with regard to lower sperm concentration, lower total sperm counts, and altered pituitary-gonadal hormones among men with high PFOS-PFOA levels. Conclusion: High PFAA levels were associated with fewer normal sperm. Thus, high levels of PFAAs may contribute to the otherwise unexplained low semen quality often seen in young men. However, our findings need to be corroborated in larger studies.
A severe decline in child births has occurred over the past half century, which will lead to considerable population declines, particularly in industrialized regions. A crucial question is whether ...this decline can be explained by economic and behavioural factors alone, as suggested by demographic reports, or to what degree biological factors are also involved. Here, we discuss data suggesting that human reproductive health is deteriorating in industrialized regions. Widespread infertility and the need for assisted reproduction due to poor semen quality and/or oocyte failure are now major health issues. Other indicators of declining reproductive health include a worldwide increasing incidence in testicular cancer among young men and alterations in twinning frequency. There is also evidence of a parallel decline in rates of legal abortions, revealing a deterioration in total conception rates. Subtle alterations in fertility rates were already visible around 1900, and most industrialized regions now have rates below levels required to sustain their populations. We hypothesize that these reproductive health problems are partially linked to increasing human exposures to chemicals originating directly or indirectly from fossil fuels. If the current infertility epidemic is indeed linked to such exposures, decisive regulatory action underpinned by unconventional, interdisciplinary research collaborations will be needed to reverse the trends.
Testicular cancer is the most common cancer among young men of European ancestry, with about one‐third of all cases occurring in Europe. With the historically increasing trends in some high‐incidence ...populations reported to have stabilised in recent years, we aimed to assess recent trends and predict the future testicular cancer incidence burden across Europe. We extracted testicular cancer (ICD‐10 C62) incidence data from Cancer Incidence in Five Continents Volumes VII–XI and complemented this with data published by registries from 28 European countries. We predicted cancer incidence rates and the number of incident cases in Europe in the year 2035 using the NORDPRED age‐period‐cohort model. Testicular cancer incidence rates will increase in 21 out of 28 countries over the period 2010–2035, with trends attenuating in the high‐incidence populations of Denmark, Norway, Switzerland and Austria. Although population ageing would be expected to reduce the number of cases, this demographic effect is outweighed by increasing risk, leading to an overall increase in the number of cases by 2035 in Europe, and by region (21, 13 and 32% in Northern, Western and Eastern Europe, respectively). Declines are however predicted in Italy and Spain, amounting to 12% less cases in 2035 in Southern Europe overall. In conclusion, the burden of testicular cancer incidence in Europe will continue to increase, particularly in historically lower‐risk countries. The largest increase in the number of testicular cancer patients is predicted in Eastern Europe, where survival is lower, reinforcing the need to ensure the provision of effective treatment across Europe.
What's new?
Testicular cancer (TC) is the most common cancer among young men of European ancestry. As the population ages, will rates of TC decrease? In this study, the authors found that, on the contrary, TC risk is predicted to rise in many European countries through the year 2035. The largest increase in the number of TC patients (32%) is predicted in Eastern Europe, where survival is also lower. These results reinforce the need to ensure that effective treatment is provided throughout Europe.
Context:
Rapidly increasing evidence has documented that endocrine-disrupting chemicals (EDCs) contribute substantially to disease and disability.
Objective:
The objective was to quantify a range of ...health and economic costs that can be reasonably attributed to EDC exposures in the European Union (EU).
Design:
A Steering Committee of scientists adapted the Intergovernmental Panel on Climate Change weight-of-evidence characterization for probability of causation based upon levels of available epidemiological and toxicological evidence for one or more chemicals contributing to disease by an endocrine disruptor mechanism. To evaluate the epidemiological evidence, the Steering Committee adapted the World Health Organization Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group criteria, whereas the Steering Committee adapted definitions recently promulgated by the Danish Environmental Protection Agency for evaluating laboratory and animal evidence of endocrine disruption. Expert panels used the Delphi method to make decisions on the strength of the data.
Results:
Expert panels achieved consensus at least for probable (>20%) EDC causation for IQ loss and associated intellectual disability, autism, attention-deficit hyperactivity disorder, childhood obesity, adult obesity, adult diabetes, cryptorchidism, male infertility, and mortality associated with reduced testosterone. Accounting for probability of causation and using the midpoint of each range for probability of causation, Monte Carlo simulations produced a median cost of €157 billion (or $209 billion, corresponding to 1.23% of EU gross domestic product) annually across 1000 simulations. Notably, using the lowest end of the probability range for each relationship in the Monte Carlo simulations produced a median range of €109 billion that differed modestly from base case probability inputs.
Conclusions:
EDC exposures in the EU are likely to contribute substantially to disease and dysfunction across the life course with costs in the hundreds of billions of Euros per year. These estimates represent only those EDCs with the highest probability of causation; a broader analysis would have produced greater estimates of burden of disease and costs.
Reproductive disorders of newborn (cryptorchidism, hypospadias) and young adult males (low sperm counts, testicular germ cell cancer) are common and/or increasing in incidence. It has been ...hypothesized that these disorders may comprise a testicular dysgenesis syndrome (TDS) with a common origin in fetal life. This has been supported by findings in an animal model of TDS involving fetal exposure to n(dibutyl) phthalate, as well as by new clinical studies. Recent advances in understanding from such studies have led to refinement of the TDS hypothesis, highlighting the central role that deficient androgen production/action during fetal testis development, may play in the origin of downstream disorders.
Phthalates are synthetic compounds widely used as plasticisers, solvents and additives in many consumer products. Several animal studies have shown that some phthalates possess endocrine disrupting ...effects. Some of the effects of phthalates seen in rats are due to testosterone lowering effects on the foetal testis and they are similar to those seen in humans with testicular dysgenesis syndrome. Therefore, exposure of the human foetus and infants to phthalates via maternal exposure is a matter of concern. The metabolic pathways of phthalate metabolites excreted in human urine are partly known for some phthalates, but our knowledge about metabolic distribution in the body and other biological fluids, including breast milk, is limited. Compared to urine, human breast milk contains relatively more of the hydrophobic phthalates, such as di‐n‐butyl phthalate and the longer‐branched, di(2‐ethylhexyl) phthalate (DEHP) and di‐iso‐nonyl phthalate (DiNP); and their monoester metabolites. Urine, however, contains relatively more of the secondary metabolites of DEHP and DiNP, as well as the monoester phthalates of the more short‐branched phthalates. This differential distribution is of special concern as, in particular, the hydrophobic phthalates and their metabolites are shown to have adverse effects following in utero and lactational exposures in animal studies.
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