Newsletter

Table of Contents

04.12.2008

Newsletter Nr. 6/2008

Maternal smoking during pregnancy specifically reduces human fetal desert hedgehog gene expression during testis development
Human fetal testis Leydig cell disruption by exposure to the pesticide dieldrin at low concentrations
Assisted reproductive technology and major structural birth defects in the United States.
Is abnormal sperm function an indicator among couples with recurrent pregnancy loss?

1. Maternal smoking during pregnancy specifically reduces human fetal desert hedgehog gene expression during testis development.

CONTEXT: Maternal cigarette smoking during gestation increases cryptorchidism and hypospadias and reduces testis size and fertility in sons by unknown mechanisms. OBJECTIVE: The objective of the study was to determine whether maternal smoking is linked with changes in male human fetal endocrinology, testis gene expression, and liver concentrations of cigarette smoke chemicals. DESIGN: This was an observational study of the male fetus, comparing pregnancies during which the mothers either did or did not smoke. SETTING: The study was conducted at the universities of Aberdeen, Glasgow, and Nottingham and Macaulay Institute (Aberdeen). PATIENTS/PARTICIPANTS: Testes, blood, and livers were collected from 69 morphologically normal human male fetuses of women undergoing elective termination of normal second-trimester pregnancies. MAIN OUTCOME MEASURES: Testosterone, human chorionic gonadotropin, LH, and cotinine; expression of 30 reproductive/developmental genes; liver concentrations of 16 polycyclic aromatic hydrocarbons; and Leydig, Sertoli. and germ cell numbers were determined. RESULTS: There were no significant differences in fetal size, testis weight, cell numbers, seminiferous tubule diameter, or circulating LH and testosterone. Fetuses from smoking mothers had smoking range cotinine levels and liver concentrations of polycyclic aromatic hydrocarbons that were significant predictors of maternal smoking (P < 0.001). Only the Sertoli cell-specific gene, desert hedgehog (DHH), was significantly altered by maternal smoking (reduced 1.8-fold, P = 0.013). CONCLUSIONS: The consequences of reduced DHH signaling in men and mice are consistent with epidemiology for effects of gestational maternal smoking on sons. Given the absence of other observed effects of maternal smoking, we concluded that reduced DHH is part of a mechanism linking maternal gestational smoking with impaired reproductive development in male offspring.

Maternal smoking during pregnancy specifically reduces human fetal desert hedgehog gene expression during testis development. J Clin Endocrinol Metab. 2008 Feb;93(2):619-26.

2. Human fetal testis Leydig cell disruption by exposure to the pesticide dieldrin at low concentrations.

BACKGROUND: Declining human reproductive health over the last 60 years has been proposed to be due to effects of environmental chemicals, especially endocrine disrupting compounds, on fetal development. We investigated whether a model pesticide, dieldrin, at concentrations within both maternal circulation and environmental ranges (1 pmol/l = 0.0004 p.p.b. = 380.9 pg/l), could disrupt the human fetal testis. METHODS: Human fetal testes were collected during the second trimester, a critical period of male sexual differentiation (development and masculinization). Testis explants were cultured for 24 h in the presence and absence of LH (10-1000 IU LH/l) and dieldrin (1 pmol and 1 nmol/l). Endocrine, immunohistological and proteome characteristics of the tissues were investigated. RESULTS: Exposure to dieldrin reduced LH-induced testosterone secretion (P < 0.05) and tissue protein concentrations of LH receptor and steroid acute regulatory protein (P < 0.05). Dieldrin altered proteins associated with cancer, apoptosis, transcription and development. Wnt-2b was reduced 3-fold and immunolocalized to Leydig and Sertoli cells. Dieldrin also reversed some LH-induced changes in protein expression, supporting the conclusion that Leydig cell function is at risk from environmental chemicals. CONCLUSIONS: Our findings indicate that exposure to very low, biologically relevant, concentrations of environmental chemicals could affect the fetal human Leydig cell, reducing testosterone secretion and potentially leading to subtle dysregulation of reproductive development and adult fecundity.

Fowler PA, Abramovich DR, Haites NE, Cash P, Groome NP, Al-Qahtani A, Murray TJ, Lea RG. Human fetal testis Leydig cell disruption by exposure to the pesticide dieldrin at low concentrations. Hum Reprod. 2007 Nov;22(11):2919-27.

3. Assisted reproductive technology and major structural birth defects in the United States.

BACKGROUND With >1% of US births occurring following use of assisted reproductive technology (ART), it is critical to examine whether ART is associated with birth defects. METHODS We analyzed data from the National Birth Defects Prevention Study, a population-based, multicenter, case-control study of birth defects. We included mothers of fetuses or live-born infants with a major birth defect (case infants) and mothers who had live-born infants who did not have a major birth defect (control infants), delivered during the period October 1997-December 2003. We compared mothers who reported ART use (IVF or ICSI) with those who had unassisted conceptions. Multiple logistic regression was used to adjust for the following confounders: maternal race/ethnicity, maternal age, smoking and parity; we stratified by plurality. RESULTS ART was reported by 1.1% of all control mothers, and by 4.5% of control mothers 35 years or older. Among singleton births, ART was associated with septal heart defects (adjusted odds ratio [aOR] = 2.1, 95% confidence intervals [CI] 1.1-4.0), cleft lip with or without cleft palate (aOR = 2.4, 95% CI 1.2-5.1), esophageal atresia (aOR = 4.5, 95% CI 1.9-10.5) and anorectal atresia (aOR = 3.7, 95% CI 1.5-9.1). Among multiple births, ART was not significantly associated with any of the birth defects studied. CONCLUSIONS These findings suggest that some birth defects occur more often among infants conceived with ART. Although the mechanism is not clear, couples considering ART should be informed of all potential risks and benefits.

Reefhuis J, Honein MA, Schieve LA, Correa A, Hobbs CA, Rasmussen SA; and the National Birth Defects Prevention Study. Assisted reproductive technology and major structural birth defects in the United States. Hum Reprod. 2008 Nov 16. [Epub ahead of print]

4. Is abnormal sperm function an indicator among couples with recurrent pregnancy loss?

OBJECTIVE: To determine whether or not sperm function parameters are altered in male partners of couples with a history of idiopathic recurrent pregnancy loss (RPL). DESIGN: In comparison with proven fertile volunteers, sperm function parameters like hypo-osmotic swelling (HOS), acrosomal status (AS), and nuclear chromatin decondensation (NCD) were assessed in vitro from male partners of couples with a history of idiopathic RPL. SETTING: Infertility clinic and andrology laboratory at National Institute of Health and Family Welfare. PATIENT(S): Male partners of couples with a history of idiopathic RPL and proven fertile male volunteers (control). INTERVENTION(S): Standard semen analysis, assessment of sperm morphology, and sperm function with tests such as HOS, AS, and NCD. MAIN OUTCOME MEASURE(S): Sperm paameters, such as HOS, AS, and NCD, were assessed in semen samples from RPL in comparison with the proven fertile control group. RESULT(S): Semen samples from the idiopathic RPL group showed below normal test scores in 57.1% of the cases for all three sperm parameters. The highest aberration (83% of cases) in sperm attributes was observed in NCD, followed by AS (45.7%) and HOS (42.9%). In contrast, abnormality in sperm morphology was limited to 5.7% of the cases. Subnormal sperm function is directly proportional with subnormal sperm motility (<50%) in 23% of the cases. Even in semen samples with normal sperm motility, sperm function scores were below normal in 31.4% of the RPL group. CONCLUSION(S): Reduction in test scores of sperm function, like HOS, AS, and NCD, in male partners of couples with idiopathic RPL suggests that sperms with altered or lowered functional competencies, if they fertilize the oocytes, may lead to the development of an unsustainable embryo resulting in early pregnancy loss. Normal sperm motility does not always ensure normal sperm function scores.

Saxena P, Misro MM, Chaki SP, Chopra K, Roy S, Nandan D. Is abnormal sperm function an indicator among couples with recurrent pregnancy loss? Fertil Steril. 2008 Nov;90(5):1854-8.

Gerhard Leyendecker