The Male Reproductive System and Endocrine Disruptors

: The male reproductive system is exposed to a great number of chemical substances which can interfere with the normal hormonal milieu and reproductive function; these are called endocrine disruptors (EDs). Despite a growing number of studies evaluating the negative effects of EDs, their production is continuously growing although some of which have been prohibited. The prevalence of poor semen quality, hypospadias, cryptorchidism, and testicular cancer have increased in the last decades, and recently, it has been postulated that these could all be part of a unique syndrome called testicular dysgenesis syndrome. This syndrome could be related to exposure to a number of EDs which cause imbalances in the hormonal milieu and oestrogenic over-exposure during the foetal stage. The same EDs can also impair spermatogenesis in offspring and have epigenetic effects. Although studies on animal and in vitro models have raised concerns, data are conflicting. However, these studies must be considered as the basis for future research to promote male reproductive health.

Phthalate Toxicity in Rats and Its Relation to Testicular Dysgenesis Syndrome in Humans

This work describes the relevance of toxicology studies of environmental chemicals, with a focus on phthalates, for a hypothesis that certain human male reproductive disorders and diseases have a common etiology of disturbance of normal development in utero. The “Testicular Dysgenesis Syndrome” hypothesis in humans has parallels in male reproductive tract abnormalities and microscopic lesions reported for phthalate toxicity in rats. Additionally, this work describes the histological findings of abnormal testicular development (testicular dysgenesis) in rats as compared to those in humans, as well as potential findings in rats at different ages, from the embryo to the adult.

O-053 Early life factors that may influence adult male reproductive

text This presentation will provide a brief overview of testicular development and will describe a critical period of development at approximately 8-14 weeks of gestation, when the testicle may be vulnerable to external influences, potentially having a negative effect on subsequent development. The talk with then describe the testicular dysgenesis syndrome hypothesis, proposed by Niels Skakkebæk, and using the presenters work within the Western Australian (Raine) Cohort will go onto demonstrate how early life exposures may influence mature testicular function. Worryingly, the presentation will describe how adolescent features of early metabolic disturbance within the Raine Cohort are already having a determinantal effect on the reproductive function of these men in late adolescence, many years before the majority are seeking paternity.

P–675 Endocrine disrupting toxic chemical affect the development of the male reproductive system but do not appear to affect the female reproductive system

Study question To assess whether geographical variations in oestrogenic disruptor contamination affect both sexes equally: on spermatogenesis and oogenesis. Summary answer There is a clear relationship between oligozoospermia and genital malformations dependent on the accumulation of endocrine disruptors in the mother, but not on ovarian reserve. What is known already Our Centre has conducted several population-based studies on semen quality, and have analysed the semen assessment and the medical history of 1,239 volunteers aged 18 to 30 years. The results showed a prevalence of oligozoospermia that was highest in Valencia (22.7%), Barcelona (22.7%) and the Basque Country (18.7%). These are the regions of Spain with the highest degree of industrialisation in the last 50 years. It was lowest in Galicia (8.5%) and Andalusia (13.7%), the regions with the least industry. Study design, size, duration This is a cross-sectional study with 10,443 healthy women aged between 20 and 45 years from eleven different communities in Spain. We determined AMH values for each age and in groups of 5 years. Linear regression analyses were used to calculate ovarian age Participants/materials, setting, methods All AMH values were assessed using an ELISA assay (AMH Gen II ELISA assay; Beckman Coulter, Brea, CA, USA). All samples were processed in the same central laboratory. Main results and the role of chance The mean age of the women was 36.6 years ± 4.3 years. Reference values for AMH, expressed as 25th, 50th, and 75th centiles by age and five year groups, were obtained. There were significant differences in AMH values between groups of women aged 30-<35 years, 35-<40 years, and 40–45 years. No significant differences were observed in AMH values in the first two age groups (20-<25 years, and 25-<30 years). The 50th centiles of mean AMH ranged from 3.45 to 0.72 ng/ml. AMH values were found to be significantly, and inversely, correlated to age (r = 0.35; p < 0.001). From the regression equation, the estimated yearly decrease in AMH was 0.2 ng/ml. The range of AMH values in Spanish women were higher than those reported for other European countries and the USA, and lower than those reported for China. Statistically significant differences were found between the results from different geographical areas but no pattern was found to justify them. It was hypothesised that in the more industrialised areas AMH levels should be lower and that this would correspond to the higher prevalence of oligozoospermia in male volunteers, but this was not the case. Limitations, reasons for caution The results for males were assigned to the geographical area where their mother was raised in all cases. For females, it was not possible to do so in all autonomous communities. Wider implications of the findings: These results suggest that oestrogenic disruptors stored in maternal fat interfere with the action of testosterone in the foetal testis inducing testicular dysgenesis syndrome. But it does not affect embryonic/fetal ovarian development, we propose that this is because higher oestrogen levels do not alter the process. Trial registration number Not applicable

Testicular dysgenesis syndrome and phthalate exposure: A review of literature

Endocrine disruptors are chemicals that interfere with the body's endocrine system and cause adverse effects in biological systems. Phthalates are a group of man-made chemicals which are mainly used as plasticizers and classified as endocrine disruptors. They are also used in cosmetic and personal care products as color or smell fixators. Moreover, phthalates are present in inks, adhesives, sealants, automobile parts, tools, toys, carpets, medical tubing and blood storage bags, and food packages. Pathological condition known as "testicular dysgenesis syndrome" (TDS) or "phthalate syndrome" is usually linked to phthalate exposure and is coined to describe the rise in alterations in reproductive health in men, such as reduced semen quality (decrease in sperm counts, sperm motility and increase in abnormal sperms), hypospadias, cryptorchidism, reduced anogenital distance and early-life testicular cancer. Phthalates are suggested to cause direct effect on gonadal and non-gonadal tissues, impair the differentiation and morphogenesis of seminiferous tubules and accessory sex organs and testicular cells (both Sertoli and Leydig cells), alter estradiol and/or testosterone levels, decrease insulin-like 3 (INSL3) peptide production, impair spermatogenesis and lead to epigenetic alterations, all of which may lead to TDS. This review will mainly focus on phthalates as causes of TDS and their mechanisms of action.

Exogenous Oestrogen Impacts Cell Fate Decision in the Developing Gonads: A Potential Cause of Declining Human Reproductive Health

The increasing incidence of testicular dysgenesis syndrome-related conditions and overall decline in human fertility has been linked to the prevalence of oestrogenic endocrine disrupting chemicals (EDCs) in the environment. Ectopic activation of oestrogen signalling by EDCs in the gonad can impact testis and ovary function and development. Oestrogen is the critical driver of ovarian differentiation in non-mammalian vertebrates, and in its absence a testis will form. In contrast, oestrogen is not required for mammalian ovarian differentiation, but it is essential for its maintenance, illustrating it is necessary for reinforcing ovarian fate. Interestingly, exposure of the bi-potential gonad to exogenous oestrogen can cause XY sex reversal in marsupials and this is mediated by the cytoplasmic retention of the testis-determining factor SOX9 (sex-determining region Y box transcription factor 9). Oestrogen can similarly suppress SOX9 and activate ovarian genes in both humans and mice, demonstrating it plays an essential role in all mammals in mediating gonad somatic cell fate. Here, we review the molecular control of gonad differentiation and explore the mechanisms through which exogenous oestrogen can influence somatic cell fate to disrupt gonad development and function. Understanding these mechanisms is essential for defining the effects of oestrogenic EDCs on the developing gonads and ultimately their impacts on human reproductive health.

Reconstitution of rat fetal testis during the masculinisation programming window induces focal dysgenesis consistent with testicular dysgenesis syndrome

Focal dysgenesis is a consistent feature of testicular dysgenesis syndrome (TDS) in humans. Rodent studies show that perturbation of androgens (e.g. following phthalate exposure) during a fetal masculinisation programming window (MPW) predisposes to a TDS phenotype. This study aimed to determine whether dissociation and reconstitution of rat fetal testis tissue during the MPW can be used to model and manipulate seminiferous cord development, including induction of focal dysgenesis, as described in TDS. Dissociated fetal rat testes were xenotransplanted subcutaneously into recipient mice for 4 weeks. Transplanted mice were treated with vehicle or di-n-butyl-phthalate (DBP, a plasticising chemical known to induce testicular dysgenesis in vivo in rats). Testosterone production by the transplants was measured in recipient mice and immunofluorescence was performed on the retrieved transplants to identify features consistent with focal testicular dysgenesis. Re-aggregation of rat fetal testis tissue xenotransplants during the MPW results in reconstitution of seminiferous cords. Features of focal testicular dysgenesis were present in re-aggregated testis, including ectopic Sertoli cells and intratubular Leydig cells (ITLCs). DBP exposure of recipient mice reduced androgen-dependent seminal vesicle weight (8.3 vs 26.7 mg; p < 0.05), but did not enhance features of focal dysgenesis including number of ITLCs (0.07 vs 0.10 cells/mm2; p > 0.05). We conclude that seminiferous cord reformation during the MPW results in development of focal dysgenesis. The system may be used to separate specific effects (e.g. androgen suppression) of individual chemical exposures from other mechanisms that may be conserved in TDS.

Effects and Mechanisms of Phthalates’ Action on Reproductive Processes and Reproductive Health: A Literature Review

The production of plastic products, which requires phthalate plasticizers, has resulted in the problems for human health, especially that of reproductive health. Phthalate exposure can induce reproductive disorders at various regulatory levels. The aim of this review was to compile the evidence concerning the association between phthalates and reproductive diseases, phthalates-induced reproductive disorders, and their possible endocrine and intracellular mechanisms. Phthalates may induce alterations in puberty, the development of testicular dysgenesis syndrome, cancer, and fertility disorders in both males and females. At the hormonal level, phthalates can modify the release of hypothalamic, pituitary, and peripheral hormones. At the intracellular level, phthalates can interfere with nuclear receptors, membrane receptors, intracellular signaling pathways, and modulate gene expression associated with reproduction. To understand and to treat the adverse effects of phthalates on human health, it is essential to expand the current knowledge concerning their mechanism of action in the organism.