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Background: Risk factors for congenital cryptorchidism were investigated in a prospective birth cohort study in Denmark and Finland from 1997 to 2001. Methodology and Principal Findings: In total, 2,496 boys were examined for cryptorchidism at birth (cryptorchid/healthy: 128/2,368) and three months old (33/2,215). Information on risk factors was obtained antenatally (questionnaire/interview) or at birth from birth records. Use of nicotine substitutes during pregnancy (n = 40) and infertility treatment by intrauterine insemination (n = 49) were associated with an increased risk for cryptorchidism, adjusted odds ratio (95% confidence interval) (OR (95%CI)) 3.04 (95%CI 1.00-9.27) and 3.01 (95%CI 1.27-7.15), respectively. No association was seen for mothers (n = 79) who had infertility treatment in form of intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF) treatment (OR 0.71 95%CI 0.21-2.38). In total, 728 (29%) reported to have smoked during pregnancy, however, no increased risk among maternal smokers was found. Furthermore, we found statistically significant associations between cryptorchidism and low birth weight, prematurity, being small for gestational age, substantial vaginal bleeding, and breech presentation, which are in accordance with other studies. Conclusions and Significance: Our study revealed two novel risk factors for cryptorchidism: intrauterine insemination and the use of nicotine substitutes in pregnancy. This suggests that cryptorchidism may not only be associated to genetic factors, but also to maternal lifestyle and exposure. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The aim of this prospective study was to investigate whether occupational pesticide exposure during pregnancy causes adverse effects on the reproductive development in the male infants. DESIGN AND MEASUREMENTS: Pregnant women employed in greenhouses in Denmark were consecutively recruited, and 113 mother-son pairs were included. The mothers were categorized as occupationally exposed (91 sons) or unexposed (22 sons) to pesticides during pregnancy. Testicular position and volume, penile length, and position of urethral opening were determined at 3 months of age using standardized techniques. Concentrations of reproductive hormones in serum from the boys were analyzed. RESULTS: The prevalence of cryptorchidism at 3 months of age was 6.2% [95% confidence interval (CI), 3.0-12.4]. This prevalence was considerably higher than among Danish boys born in the Copenhagen area (1.9%; 95% CI, 1.2-3.0) examined by the same procedure. Boys of pesticideexposed mothers showed decreased penile length, testicular volume, serum concentrations of testosterone, and inhibin B. Serum concentrations of sex hormone-binding globulin, follicle-stimulating hormone, and the luteinizing hormone:testosterone ratio were increased compared with boys of nonexposed mothers. For individual parameters, only the decreased penile length was statistically significant (p = 0.04). However, all observed effects were in the anticipated direction, and a joint multivariate test showed that this finding had a p-value of 0.012. CONCLUSIONS: Our findings suggest an adverse effect of maternal occupational pesticide exposure on reproductive development in the sons despite current greenhouse safeguards and special measures to protect pregnant women. [ABSTRACT FROM AUTHOR]

BACKGROUND: Prenatal exposure to alcohol can adversely affect the fetus. We investigated the association between maternal alcohol consumption during pregnancy and cryptorchidism (undescended testis) among newborn boys. METHODS: We examined 2,496 boys in a prospective Danish--Finnish birth cohort study for cryptorchidism at birth (cryptorchid/healthy: 128/2,368) and at 3 months of age (33/2,215). Quantitative information on alcohol consumption (average weekly consumption of wine, beer, and spirits and number of binge episodes), smoking, and caffeine intake was obtained by questionnaire and/or interview once during the third trimester of pregnancy, before the outcome of the pregnancy was known. For a subgroup (n = 465), information on alcohol consumption was obtained twice during pregnancy by interviews. RESULTS: We investigated maternal alcohol consumption both as a continuous variable and categorized. The odds for cryptorchidism increased with increasing weekly alcohol consumption. After adjustment for confounders (country, smoking, caffeine intake, binge episodes, social class, maternal age, parity, maturity, and birth weight) the odds remained significant for women with a weekly consumption of five or more alcoholic drinks (odds ratio = 3.10; 95% confidence interval, 1.05-9.10). CONCLUSIONS: Regular alcohol intake during pregnancy appears to increase the risk of congenital cryptorchidism in boys. The mechanisms for this association are unknown. Counseling of pregnant women with regard to alcohol consumption should also consider this new finding. [ABSTRACT FROM AUTHOR]

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; β-hexachlorocyclohexane (β-HCH): 13.6/12.3; hexachlorobenzene (HCB): 10.6/8.8; α-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), γ-HCH, 1,1-dichloro-2-(2-chlorophenyl)-2,2(4-chlorophenyl)ethane, trans-chlordane, α-HCH, and o,p′-DDE, both concentrations and detection rates were low (26.5–71.5%). Heptachlor, HCH (δ, ϵ), aldrin, β-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 (α, β, γ), HCB, PCA, α-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. [ABSTRACT FROM AUTHOR]

The etiology of cryptorchidism remains poorly understood. Endocrine disrupting chemicals can impact estrogen signaling by interacting with aryl hydrocarbon receptor (AhR) activity. To evaluate whether AhR activity in breast milk samples is associated with cryptorchidism. We conducted a case-control study based on 199 mother-child pairs (n = 91 cases/108 controls) selected from the Norwegian Human Milk Study (2002–2009). We defined cases for cryptorchidism based on maternal reports at 1-, 6-, 12-, and 24- months after birth. Chemically- and biologically stable AhR activity (pg 2,3,7,8-TCDD equivalent (TEQ)/g lipid) was determined by DR- CALUX® assay in the mothers' milk collected at a median of 33 (10th–90th percentile: 18–57) days after delivery. We used multivariate logistic regression to compare AhR activity levels between cases and controls, and linear regression separately, to establish the relationship with the presence of 27 potential EDCs measured in breast milk and AhR activity. The average estimated daily intake (EDI) of dioxin and (dioxin-like (dl)-compounds via breast milk is 33.7 ± 17.9 pg TEQ/kg bodyweight per day among Norwegian children. There were no significant differences in AhR activation in breast milk samples between cases with cryptorchidism and controls. Among the 27 chemicals measured in breast milk, AhR activity was (borderline) significantly associated with all dl-PCBs, three non-dioxin-like (ndl)-PCBs (PCB-74, PCB-180, PCB-194) and two organochlorine pesticides (OCPs; HCB, β-HCH). No associations between AhR activity and brominated flame retardants (PBDEs) or poly- and perfluoroalkyl substances (PFASs). No association between AhR activity and cryptorchidism was found among Norwegian boys. The average EDI of dioxin and dl-compounds in exclusively breastfed Norwegian infants remains above the safety threshold and, therefore requires further reduction measures. Consistent with a possible role in the observed AhR activity, all dl-PCBs were associated with AhR activity whereas the association was null for either PBDEs or PFASs. • Norwegian breast milk levels of dioxin and dioxin-like compounds are above tolerable daily intake for infants. • The average estimated daily intake of dioxin and dl-compounds via breast milk is 33.7 ± 17.9 pg CALUX-TEQ/kg bw/day. • There was no association between activation of aryl hydrocarbon receptor by breast milk extracts and cryptorchidism. • Measured AhR activity (pg CALUX-TEQ/g lipid) is used as an indirect measurement of dioxins and dl-PCBs in breast milk. • Breast milk also contains wide range of AhR agonist chemicals such as the estrogenic poly aromatic hydrocarbons. [ABSTRACT FROM AUTHOR]

• Exposure to endocrine-disrupting chemicals may increase the risk of cryptorchidism. • Breast milk levels of persistent chemicals represent prenatal & postnatal exposure. • The estrogenic organochlorine pesticide β-HCH is associated with cryptorchidism. • PCB-74, PCB-114, and PCB-194 may also increase the risk of cryptorchidism. • Single pollutant analysis results can be confounded by highly correlated chemicals. Exposure to endocrine-disrupting chemicals (EDCs) during the critical period of testicular descent may increase the risk of cryptorchidism and male fertility. To investigate 27 potential EDCs measured in breast milk as a proxy for perinatal exposure and the risk of cryptorchidism in a prospective cohort. The Norwegian Human Milk Study (2002–2009) enrolled 2606 mother-infant pairs, of which 1326 were mother-son pairs. In a case-cohort design, we studied 641 male infants who had 27 EDCs already quantified in milk samples: 5 organochlorine pesticides, 14 polychlorinated biphenyls (PCBs), 6 brominated flame retardants, and 2 poly- and perfluoroalkyl substances. We defined cases of congenital, recurrent, persistent and ever-reported cryptorchidism based on questionnaires mothers completed when children were 1, 6, 12 and 24 months old. Variable selection via elastic net logistic regression identified the best cryptorchidism predictors while multivariable logistic regression models determined their effect estimates. The prevalence of reported congenital cryptorchidism was 6.1%, with half spontaneously descending within six months of birth, after which prevalence stabilized between 2.2 and 2.4%. The ever-reported prevalence of cryptorchidism at 1, 6, 12, or 24 months was 12.2%. Elastic net models identified PCB-74 (OR = 1.31, 95% CI: 1.001–1.703), PCB-114 (OR = 1.36, 95% CI: 1.05–1.77), PCB-194 (OR = 1.28, 95% CI: 1.03–1.53) and β-HCH (OR = 1.26, 95% CI: 1.03–1.53 (per interquartile range increase in concentration of EDCs) as best predictors of congenital cryptorchidism. No EDCs were selected for either recurrent or persistent cryptorchidism, and only PCB-194 was selected by elastic net for ever-reported cryptorchidism (OR = 1.23, 95% CI: 1.01–1.51), in contrast to unpenalized multivariable logistic regression, where most of the individual congeners of PCBs showed significant associations. In the largest multi-pollutant analysis to date considering potential confounding from co-exposure to other chemicals, perinatal exposure to PCB-74, PCB-114, PCB-194 and β-HCH were associated with increased odds of congenital cryptorchidism. Many PCBs may falsely be associated with cryptorchidism when assessed individually, due to confounding by highly correlated chemicals. Experimental studies are warranted to confirm our findings. [ABSTRACT FROM AUTHOR]