Helena E. Virtanen

UNLABELLED: Phthalates adversely affect the male reproductive system in animals. We investigated whether phthalate monoester contamination of human breast milk had any influence on the postnatal surge of reproductive hormones in newborn boys as a sign of testicular dysgenesis. DESIGN: We obtained biologic samples from a prospective Danish-Finnish cohort study on cryptorchidism from 1997 to 2001. We analyzed individual breast milk samples collected as additive aliquots 1-3 months postnatally (n = 130; 62 cryptorchid/68 healthy boys) for phthalate monoesters [mono-methyl phthalate (mMP), mono-ethyl phthalate (mEP), mono-n-butyl phthalate (mBP), mono-benzyl phthalate (mBzP), mono-2-ethylhexyl phthalate (mEHP), mono-isononyl phthalate (miNP)]. We analyzed serum samples (obtained in 74% of all boys) for gonadotropins, sex-hormone binding globulin (SHBG), testosterone, and inhibin B. RESULTS: All phthalate monoesters were found in breast milk with large variations [medians (minimum-maximum)]: mMP 0.10 (< 0.01-5.53 microg/L), mEP 0.95 (0.07-41.4 microg/L), mBP 9.6 (0.6-10,900 microg/L), mBzP 1.2 (0.2-26 microg/L), mEHP 11 (1.5-1,410 microg/L), miNP 95 (27-469 microg/L). Finnish breast milk had higher concentrations of mBP, mBzP, mEHP, and Danish breast milk had higher values for miNP (p = 0.0001-0.056). No association was found between phthalate monoester levels and cryptorchidism. However, mEP and mBP showed positive correlations with SHBG (r = 0.323, p = 0.002 and r = 0.272, p = 0.01, respectively); mMP, mEP, and mBP with LH:free testosterone ratio (r = 0.21-0.323, p = 0.002-0.044) and miNP with luteinizing hormone (r = 0.243, p = 0.019). mBP was negatively correlated with free testosterone (r = -0.22, p = 0.033). Other phthalate monoesters showed similar but nonsignificant tendencies. CONCLUSIONS: Our data on reproductive hormone profiles and phthalate exposures in newborn boys are in accordance with rodent data and suggest that human Leydig cell development and function may also be vulnerable to perinatal exposure to some phthalates. Our findings are also in line with other recent human data showing incomplete virilization in infant boys exposed to phthalates prenatally.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are widely used in Western countries. OBJECTIVES: Because the prevalence of cryptorchidism appears to be increasing, we investigated whether exposure to PBDEs was associated with testicular maldescent. METHODS: In a prospective Danish-Finnish study, 1997-2001, all boys were examined for cryptorchidism. We analyzed whole placentas (for 95 cryptorchid/185 healthy boys) and individual breast milk samples (62/68) for 14 PBDEs and infant serum samples for gonadotropins, sex-hormone binding globulin, testosterone, and inhibin B. RESULTS: In 86 placenta-milk pairs, placenta PBDE concentrations in fat were lower than in breast milk, and a larger number of congeners were nondetectable. There was no significant difference between boys with and without cryptorchidism for individual congeners, the sum of 5 most prevalent, or all 14 congeners. The concentration of PBDEs in breast milk was significantly higher in boys with cryptorchidism than in controls (sum of BDEs 47, 153, 99, 100, 28, 66, and 154: median, 4.16 vs. 3.16 ng/g fat; p < 0.007). There was a positive correlation between the sum of PBDEs and serum luteinizing hormone (p < 0.033). The sum of PBDEs in breast milk did not differ between Denmark and Finland (median, 3.52 vs. 3.44 ng/g fat), but significant differences in some individual congeners were found. CONCLUSIONS: Two different proxies were used for prenatal PBDE exposure, and levels in breast milk, but not in placenta, showed an association with congenital cryptorchidism. Other environmental factors may contribute to cryptorchidism. Our observations are of concern because human exposure to PBDEs is high in some geographic areas.

AIM: To reach consensus among specialists from the Nordic countries on the present state-of-the-art in treatment of undescended testicles. METHODS: A group of specialists in testicular physiology, paediatric surgery/urology, endocrinology, andrology, pathology and anaesthesiology from all the Nordic countries met for two days. Before the meeting, reviews of the literature had been prepared by the participants. RECOMMENDATIONS: The group came to the following unanimous conclusions: (1) In general, hormonal treatment is not recommended, considering the poor immediate results and the possible long term adverse effects on spermatogenesis. Thus, surgery is to be preferred. (2) Orchiopexy should be done between 6 and 12 months of age, or upon diagnosis, if that occurs later. (3) Orchiopexy before age one year should only be done at centres with both paediatric surgeons/urologists and paediatric anaesthesiologists. (4) If a testis is found to be undescended at any age after 6 months, the patient should be referred for surgery--to paediatric rather than general surgeons/urologists if the boy is less than one year old or if he has bilateral or non-palpable testes, or if he has got relapse of cryptorchidism.

Production of sperm and androgens is the main function of the testis. This depends on normal development of both testicular somatic cells and germ cells. A genetic program initiated from the Y chromosome gene sex-determining region Y (SRY) directs somatic cell specification to Sertoli cells that orchestrate further development. They first guide fetal germ cell differentiation toward spermatogenic destiny and then take care of the full service to spermatogenic cells during spermatogenesis. The number of Sertoli cells sets the limits of sperm production. Leydig cells secrete androgens that determine masculine development. Testis development does not depend on germ cells; that is, testicular somatic cells also develop in the absence of germ cells, and the testis can produce testosterone normally to induce full masculinization in these men. In contrast, spermatogenic cell development is totally dependent on somatic cells. We herein review germ cell differentiation from primordial germ cells to spermatogonia and development of the supporting somatic cells. Testicular descent to scrota is necessary for normal spermatogenesis, and cryptorchidism is the most common male birth defect. This is a mild form of a disorder of sex differentiation. Multiple genetic reasons for more severe forms of disorders of sex differentiation have been revealed during the last decades, and these are described along with the description of molecular regulation of testis development.

INTRODUCTION: Prenatal exposure to some pesticides can adversely affect male reproductive health in animals. We investigated a possible human association between maternal exposure to 27 organochlorine compounds used as pesticides and cryptorchidism among male children. DESIGN: Within a prospective birth cohort, we performed a case-control study; 62 milk samples from mothers of cryptorchid boys and 68 from mothers of healthy boys were selected. Milk was collected as individual pools between 1 and 3 months postpartum and analyzed for 27 organochlorine pesticides. RESULTS: Eight organochlorine pesticides were measurable in all samples (medians; nanograms per gram lipid) for cases/controls: 1,1-dichloro-2,2-bis(4-chlorophenyl) ethylene (p,p -DDE) : 97.3/83.8; beta-hexachlorocyclohexane (beta-HCH) : 13.6/12.3; hexachlorobenzene (HCB) : 10.6/8.8; alpha-endosulfan: 7.0/6.7; oxychlordane: 4.5/4.1; 1,1,1-trichloro-2,2-bis(4-chlorophenyl) ethane (p,p -DDT) : 4.6/4.0; dieldrin: 4.1/3.1 ; cis-heptachloroepoxide (cis-HE) : 2.5/2.2. Five compounds [octachlorostyrene (OCS); pentachlorobenzene, 1,1-dichloro-2,2-bis(4-chlorophenyl) ethane(p,p -DDD) ; o,p -DDT ; mirex] were measurable in most samples (detection rates 90.8-99.2%) but in lower concentrations. For methoxychlor, cis-chlordane, pentachloroanisole (PCA), gamma-HCH, 1,1-dichloro-2-(2-chlorophenyl) -2,2(4-chlorophenyl) ethane, trans-chlordane, alpha-HCH, and o,p -DDE, both concentrations and detection rates were low (26.5-71.5%). Heptachlor, HCH (lc delta, epsilon), aldrin, beta-endosulfan and trans-heptachloroepoxide were detected at negligible concentrations and low detection rates and were not analyzed further. Seventeen of 21 organochlorine pesticides [p,p -DDT, p,p-DDE, p,p-DDD, o,p-DDT, HCH (alpha, beta, gamma), HCB, PCA, alpha-endosulfan, cis-HE, chlordane (cis-, trans-) oxychlordane, methoxychlor, OCS, and dieldrin] were measured in higher median concentrations in case milk than in control milk. Apart from trans-chlordane (p = 0.012), there were no significant differences between cryptorchid and healthy boys for individual chemicals. However, combined statistical analysis of the eight most abundant persistent pesticides showed that pesticide levels in breast milk were significantly higher in boys with cryptorchidism (p = 0.032). CONCLUSION: The association between congenital cryptorchidism and some persistent pesticides in breast milk as a proxy for maternal exposure suggests that testicular descent in the fetus may be adversely affected.