Maternal occupational exposure to endocrine-disrupting chemicals during pregnancy and semen parameters in adulthood: results of a nationwide cross-sectional study among Swiss conscripts.

STUDY QUESTION: Is there a relationship between maternal occupational exposure to endocrine-disrupting chemicals (EDCs) during pregnancy and the semen quality of their sons? SUMMARY ANSWER: Our results suggest an association between maternal occupational exposure to potential EDCs, especially to pesticides, phthalates and heavy metals, and a decrease in several semen parameters. WHAT IS KNOWN ALREADY: Sexual differentiation, development and proper functioning of the reproductive system are largely dependent on steroid hormones. Although there is some animal evidence, studies on maternal exposure to EDCs during pregnancy and its effect on the semen quality of sons are scarce and none have focused on maternal occupational exposure. STUDY DESIGN, SIZE, DURATION: A cross-sectional study aiming to evaluate semen quality was carried out among Swiss conscripts aged 18 to 22 years between 2005 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Conscript and parent questionnaires were completed prior to the collection of a semen sample. Semen parameters were categorised according to the guidelines of the World Health Organization (WHO). Data on maternal employment during pregnancy were provided by the parent questionnaire. Maternal occupational exposure to potential EDC categories was defined using a job-exposure matrix (JEM). Logistic regressions were used to analyse the relationship between maternal occupational exposure to EDCs and each semen parameter adjusted for potential confounding factors. Results are presented using odds ratios and 95% confidence intervals. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 1,737 conscripts provided a conscript and parent questionnaire, as well as a semen sample; among these 1,045 of their mothers worked during pregnancy. Our study suggests an association between occupational exposure of mothers during pregnancy to potential EDCs and low semen volume and total sperm count, particularly for exposure to pesticides (OR 2.07, 95% CI 1.11-3.86 and OR 2.14, 95% CI 1.05-4.35), phthalates (OR 1.92, 95% CI 1.10-3.37 and OR 1.89, 95% CI 1.01-3.55), and heavy metals (OR 2.02, 95% CI 1.14-3.60 and OR 2.29, 95% CI 1.21-4.35). Maternal occupational exposure to heavy metals was additionally associated with a low sperm concentration (OR 1.89, 95% CI 1.06-3.37). LIMITATIONS, REASONS FOR CAUTION: Several limitations should be noted, such as the indirect method for maternal occupational exposure assessment during the pregnancy (JEM) and the cross-sectional design of the study. WIDER IMPLICATIONS OF THE FINDINGS: Our observations reinforce the need to inform pregnant women of potential hazards during pregnancy that could impair their child's fertility. Additional studies are needed to confirm the involvement of EDCs. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Swiss Centre for Applied Human Toxicology: SCAHT and the 'Fondation privée des Hôpitaux Universitaires de Genève'. The collection of human biological material used for this study was supported by the FABER Foundation, the Swiss National Science Foundation (SNSF): NFP 50 'Endocrine Disruptors: Relevance to Humans, Animals and Ecosystems', the Medical Services of the Swiss Army (DDPS) and Medisupport. The authors declare they have no competing financial interests. TRIAL REGISTRATION NUMBER: N/A.

Semen quality of young men in Switzerland: a nationwide cross-sectional population-based study.

BACKGROUND: Sperm counts have been steadily decreasing over the past five decades with regional differences in the Western world. The reasons behind these trends are complex, but numerous insights indicate that environmental and lifestyle factors are important players. OBJECTIVE: To evaluate semen quality and male reproductive health in Switzerland. MATERIALS AND METHODS: A nationwide cross-sectional study was conducted on 2523 young men coming from all regions of Switzerland, recruited during military conscription. Semen volume, sperm concentration, motility, and morphology were analyzed. Anatomy of the genital area and testicular volume was recorded. Testicular cancer incidence rates in the general population were retrieved from Swiss regional registries. RESULTS: Median sperm concentration adjusted for period of sexual abstinence was 48 million/mL. Comparing with the 5th percentile of the WHO reference values for fertile men, 17% of men had sperm concentration below 15 million/mL, 25% had less than 40% motile spermatozoa, and 43% had less than 4% normal forms. Disparities in semen quality among geographic regions, urbanization rates, and linguistic areas were limited. A larger proportion of men with poor semen quality had been exposed in utero to maternal smoking. Furthermore, testicular cancer incidence rates in the Swiss general population increased significantly between 1980 and 2014. DISCUSSION: For the first time, a systematic sampling among young men has confirmed that semen quality is affected on a national level. The median sperm concentration measured is among the lowest observed in Europe. No specific geographical differences could be identified. Further studies are needed to determine to what extent the fertility of Swiss men is compromised and to evaluate the impact of environmental and lifestyle factors. CONCLUSION: A significant proportion of Swiss young men display suboptimal semen quality with only 38% having sperm concentration, motility, and morphology values that met WHO semen reference criteria.

mKlf7, a potential transcriptional regulator of TrkA nerve growth factor receptor expression in sensory and sympathetic neurons.

Development of the nervous system relies on stringent regulation of genes that are crucial to this process. TrkA, the receptor for nerve growth factor (NGF), is tightly regulated during embryonic development and is essential for the survival and differentiation of neural crest-derived sensory and sympathetic neurons. We have previously identified a mouse TrkA enhancer and have characterized several cis regulatory elements that are important for appropriate TrkA expression in vivo. We now report the cloning of a novel gene encoding a Kruppel-like factor from a mouse dorsal root ganglion expression library. This Kruppel-like factor, named mKlf7, binds specifically to an Ikaros core binding element that is crucial for in vivo TrkA enhancer function. Using in situ hybridization, we demonstrate that mKlf7 is coexpressed with TrkA in sensory and sympathetic neurons during embryogenesis and in adulthood. These data are consistent with the idea that mKlf7 may directly regulate TrkA gene expression in the peripheral nervous system.

Hormones in male sexual development.

Classical embryology has provided a clear view of the timing and hormonal cues that govern sexual differentiation. Molecular biology has added important details to this picture. The cloning of SRY, MIS, and INSL3 provide insight into the molecular signals that provide important cues at the cellular level. Continued understanding of these pathways may provide the necessary information to one day reverse defects of sexual differentiation.

A molecular basis for estrogen-induced cryptorchidism.

Male sexual differentiation relies upon testicular secretion of the hormones testosterone, Mullerian inhibiting substance, and insulin-3 (Insl3). Insl3 is responsible for testicular descent through virilization and outgrowth of the embryonic gubernaculum. In mouse, prenatal exposure to 17beta-estradiol and the nonsteroidal synthetic estrogen diethylstilbestrol (DES) disturbs the endocrine balance, causing demasculinizing and feminizing effects in the male embryo, including impaired testicular descent (cryptorchidism). In the current study, we show that maternal exposure to estrogens, including 17alpha- and beta-estradiol, as well as DES, specifically down regulates Insl3 expression in embryonic Leydig cells, thereby providing a mechanism for cryptorchidism. These experiments may have implications for the widespread use of estrogenic substances in agriculture and the environment.

Cryptorchidism in mice mutant for Insl3.

Impaired testicular descent (cryptorchidism) is one of the most frequent congenital abnormalities in humans, involving 2% of male births. Cryptorchidism can result in infertility and increases risk for development of germ-cell tumours. Testicular descent from abdomen to scrotum occurs in two distinct phases: the trans-abdominal phase and the inguino-scrotal phase. Currently, little is known about the factors that regulate the trans-abdominal phase of testicular descent. Leydig insulin-like hormone (Insl3) is a member of the insulin hormone superfamily expressed in the developing testis. We show here that mice mutant for Insl3 are viable, but exhibit bilateral cryptorchidism due to developmental abnormalities of the gubernaculum, resulting in abnormal spermatogenesis and infertility. Female homozygotes have impaired fertility associated with deregulation of the oestrus cycle. These findings reveal roles for Insl3 in the development of the urogenital tract and in female fertility. Insl3 may act as a hormone to regulate the growth and differentiation of the gubernaculum, thereby mediating intra-abdominal testicular descent.

cpp32 messenger RNA neosynthesis is induced by fatal axotomy and is not regulated by athanatal Bcl-2 over-expression.

In vivo, neuronal over-expression of the anti-apoptotic protein Bcl-2 prevents axotomy-induced motoneuron death and prolongs life in a mouse model of familial amyotrophic lateral sclerosis. The mechanism of these protective effects is still unknown. We have examined, in situ, the influence of Bcl-2 over-expression on the messenger RNA level of two pro-apoptotic, bax and cpp32, and one anti-apoptotic, bcl-xl, regulators of neuronal death. In neonates wild-type mice, cpp32 mRNA was increased in axotomized, dying motoneurons. No changes in bax and bcl-xl messenger RNAs expression were detected. A similar course was observed in protected axotomized neonate motoneurons of transgenic mice over-expressing Bcl-2. In adult wild-type mice no motoneuron death was detected one week after axotomy: bax and cpp32 messenger RNAs were increased and bcl-xl messenger RNA was decreased. Four weeks after the lesion, 60% of the lesioned facial motoneurons had disappeared. In the remaining motoneurons only cpp32 messenger RNA expression was superior to control level. In Bcl-2 transgenic mice, no axotomy-induced facial motoneurons death was detected but the course of the neosynthesis of cell death genes messenger RNAs was similar to wild-type mice. Bax, Bcl-x and CPP32 immunoreactivity were increased in facial motoneurons after axotomy. Thus, fatal axotomy induces cell death genes bax and cpp32 messenger RNAs neosynthesis which is not prevented by athanatal Bcl-2 over-expression. This suggests that the protective effect of Bcl-2 results from interactions with Bax and CPP32 at the post-translation level without repercussion at the messenger RNA level. Axotomy induces cell death messenger RNA neosynthesis potentially harmful at long-term despite Bcl-2 over-expression.

Regulation of rhodopsin phosphorylation by a family of neuronal calcium sensors.

Recoverin is a calcium sensor that regulates rhodopsin phosphorylation in a calcium-dependent manner. Cloning experiments indicate the presence of a numerous gene family, called the NCS family, encoding recoverin-like proteins expressed predominantly in neurons. Here, we report the cloning of three novel NCS genes, and demonstrate that at least six distinct members of the NCS family (including recoverin, S-modulin, vilip 1, NCS-1, Ce-NCS-1, and Ce-NCS-2) specifically inhibit rhodopsin phosphorylation. The presence of species homologues within the NCS family suggests that this function might be shared by at least 12 (out of 18) NCS proteins. Recent studies indicate that recoverin inhibits rhodopsin phosphorylation by directly regulating rhodopsin kinase, a G protein coupled receptor kinase (GRK). Since several NCS proteins are found in neurons throughout the entire nervous system, they may regulate other members of the GRK family. Together, our data suggest a general role for NCS proteins in the regulation of calcium-dependent phosphorylation in the nervous system.