Reproductive Health Risks Associated with Occupational and Environmental Exposure to Pesticides.

A marked reduction in fertility and an increase in adverse reproductive outcomes during the last few decades have been associated with occupational and environmental chemical exposures. Exposure to different types of pesticides may increase the risks of chronic diseases, such as diabetes, cancer, and neurodegenerative disease, but also of reduced fertility and birth defects. Both occupational and environmental exposures to pesticides are important, as many are endocrine disruptors, which means that even very low-dose exposure levels may have measurable biological effects. The aim of this review was to summarize the knowledge collected between 2000 and 2020, to highlight new findings, and to further interpret the mechanisms that may associate pesticides with infertility, abnormal sexual maturation, and pregnancy complications associated with occupational, environmental and transplacental exposures. A summary of current pesticide production and usage legislation is also included in order to elucidate the potential impact on exposure profile differences between countries, which may inform prevention measures. Recommendations for the medical surveillance of occupationally exposed populations, which should be facilitated by the biomonitoring of reduced fertility, is also discussed.

Urinary metabolites of non-persistent pesticides and serum hormones in Spanish adolescent males.

OBJECTIVE: To assess the relationship of urinary concentrations of ethylenethiourea (ETU), the main degradation product of ethylene bis-dithiocarbamate fungicides, 3-phenoxybenzoic acid (3-PBA), a common metabolite of many pyrethroids, and 1-naphthol (1N), a metabolite of the carbamate insecticide carbaryl, with hormone concentrations in adolescent males; and to examine interactions between pesticide metabolites and polymorphisms in xenobiotic metabolizing enzymes, including CYP2C19 and CYP2D6, in relation to hormone concentrations. METHODS: A cross-sectional study was conducted in 134 males from the Spanish Environment and Childhood (INMA)-Granada cohort. Urine and serum samples were collected from participants during the same clinical visit at the age of 15-17 years. First morning urine void was analyzed for concentrations of ETU, 3-PBA, and 1N. Serum was analyzed for concentrations of reproductive hormones (testosterone, 17ß-estradiol [E2], dehydroepiandrosterone sulfate [DHEAS], sex hormone binding globulin [SHBG], luteinizing hormone [LH], follicle stimulating hormone [FSH], anti-Müllerian hormone [AMH], and prolactin), thyroid hormones (free thyroxine [FT4], total triiodothyronine [TT3], and thyroid stimulating hormone [TSH]), insulin growth factor 1 (IGF-1), adrenocorticotropic hormone (ACTH), and cortisol. CYP2C19 G681A and CYP2D6 G1846A polymorphisms were determined in blood from 117 participants. Multiple linear regression, interaction terms, and stratified analyses were performed. RESULTS: Urinary ETU was detected in 74.6% of participants, 1N in 38.1%, and 3-PBA in 19.4%. Positive associations between detectable 3-PBA and TT3 and between detectable 1N and DHEAS were found, and marginally-significant associations of 1N with reduced E2 and FSH were observed. Poor CYP2C19 and CYP2D6 metabolizers (GA and AA genotype carriers) showed a greater increase in DHEAS for detected versus undetected 1N compared with GG genotype carriers. Poor CYP2D6 metabolizers (1846 GA and AA genotypes) evidenced increased cortisol for detected versus undetected ETU. CONCLUSIONS: The associations observed between urinary pesticide metabolites and altered thyroid and reproductive hormones are novel and should be verified in studies with larger sample size. Further research on gene-environment interactions is warranted to establish individual susceptibility to pesticides and the risk of adverse health effects.

The LH/FSH ratio is not a sex-dimorphic marker after infancy: data from 6417 healthy individuals and 125 patients with Differences of Sex Development.

STUDY QUESTION: What is the course of the LH/FSH ratio from infancy into adulthood in healthy individuals and in patients with Differences of Sex Development (DSD)? SUMMARY ANSWER: The LH/FSH ratio had a marked overlap between the sexes after infancy and onwards throughout adulthood in healthy individuals and it was not a marker of hypogonadism in DSD patients. WHAT IS KNOWN ALREADY: The LH/FSH ratio is a distinct marker of sex during minipuberty. No study has evaluated the LH/FSH ratio from infancy into adulthood. STUDY DESIGN, SIZE, DURATION: This was a combined study of prospective longitudinal and cross-sectional cohorts of healthy individuals totaling 6417 males and females aged 0-80 years. Retrospective data from a single, tertiary center on 125 patients with DSD was also included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on the healthy males (n = 3144) and females (n = 3273) aged 0-80 years, reference ranges for LH, FSH and the LH/FSH ratio were established from infancy (after minipuberty) and onwards. LH, FSH, and the LH/FSH ratio in 125 patients with DSD not undergoing treatment were compared to the reference ranges. Included DSD diagnoses were: Klinefelter syndrome including mosaic variants (males: n = 14), Turner syndrome including mosaic variants without Y-chromosome material (females: n = 48), 45,X/46,XY mosaicism (males: n = 24 and females: n = 6), partial androgen insensitivity syndrome (males: n = 11), complete androgen insensitivity syndrome (females: n = 13) and anorchia (males: n = 9). MAIN RESULTS AND THE ROLE OF CHANCE: An overlap was observed in the LH/FSH ratio reference curves between males and females. However, when comparing the sexes at specific time points, the LH/FSH ratio was significantly higher in healthy males during childhood and adulthood and significantly higher in healthy females during puberty. When compared with healthy participants, male patients with anorchia and 45,X/46,XY mosaicism had significantly lower ratios, while patients with androgen insensitivity, regardless of sex, had significantly higher ratios. LIMITATIONS, REASONS FOR CAUTION: The limitations of this study include that; (i) all healthy individuals were Caucasian, so conclusions may not apply to non-Caucasians; (ii) the calculated LH/FSH ratios were restricted to the specific analytical method used and may not be applicable to other laboratories; (iii) the samples from healthy individuals were stored for varying amounts of time up to 20 years which may affect the durability; and (iv) DSD diagnoses are heterogeneous thus making sturdy conclusions across diagnoses impossible. WIDER IMPLICATIONS OF THE FINDINGS: In this study of combined cohorts of healthy participants, the largest normative ranges of LH, FSH, and the LH/FSH ratio to date were created. These reference ranges provide the opportunity for clinical as well as research use for all three markers. However, the previously rather undescribed LH/FSH ratio was not a distinct marker of sex after infancy nor a new marker of hypogonadism. Although there were significant differences between subgroups of DSD patients compared to healthy controls, the clinical significance of the LH/FSH ratio after infancy lacked. However, it can be speculated whether there are other areas of clinical application not investigated in this article, for example as a marker of fertility in select patient groups. As gonadotropin assays are readily available and gonadotropin measurements are part of regular workups, the LH/FSH ratio can easily be explored in further research without additional costs. STUDY FUNDING/COMPETING INTEREST(S): M.L.L. was funded by the Absalon Foundation. Cohort 1 was funded by the European Commission, through the Biomed 2 Program (BMH4-CT96-0314), Environmental Reproductive Health (QLK4-CT1999-01422) and EXPORED (QLK4-2001-00269), by the Danish Council for Independent Research (9700833 and 9700909), and by the Svend Andersens Foundation. Cohort 2 was funded by the Danish Environmental Research Program (96.01.015.16.05). Cohort 3 was funded by Kirsten and Freddy Johansens Foundation. TRIAL REGISTRATION NUMBER: NA. DATE OF FIRST PATIENT'S ENROLMENT: June 1990 (the launch of the department from which this project stems).

AOP4EUpest: mapping of pesticides in adverse outcome pathways using a text mining tool.

MOTIVATION: Exposure to pesticides may lead to adverse health effects in human populations, in particular vulnerable groups. The main long-term health concerns are neurodevelopmental disorders, carcinogenicity as well as endocrine disruption possibly leading to reproductive and metabolic disorders. Adverse outcome pathways (AOP) consist in linear representations of mechanistic perturbations at different levels of the biological organization. Although AOPs are chemical-agnostic, they can provide a better understanding of the Mode of Action of pesticides and can support a rational identification of effect markers. RESULTS: With the increasing amount of scientific literature and the development of biological databases, investigation of putative links between pesticides, from various chemical groups and AOPs using the biological events present in the AOP-Wiki database is now feasible. To identify co-occurrence between a specific pesticide and a biological event in scientific abstracts from the PubMed database, we used an updated version of the artificial intelligence-based AOP-helpFinder tool. This allowed us to decipher multiple links between the studied substances and molecular initiating events, key events and adverse outcomes. These results were collected, structured and presented in a web application named AOP4EUpest that can support regulatory assessment of the prioritized pesticides and trigger new epidemiological and experimental studies. AVAILABILITY AND IMPLEMENTATION: http://www.biomedicale.parisdescartes.fr/aop4EUpest/home.php. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Interaction between prenatal pesticide exposure and a common polymorphism in the PON1 gene on DNA methylation in genes associated with cardio-metabolic disease risk-an exploratory study.

BACKGROUND: Prenatal environmental conditions may influence disease risk in later life. We previously found a gene-environment interaction between the paraoxonase 1 (PON1) Q192R genotype and prenatal pesticide exposure leading to an adverse cardio-metabolic risk profile at school age. However, the molecular mechanisms involved have not yet been resolved. It was hypothesized that epigenetics might be involved. The aim of the present study was therefore to investigate whether DNA methylation patterns in blood cells were related to prenatal pesticide exposure level, PON1 Q192R genotype, and associated metabolic effects observed in the children. METHODS: Whole blood DNA methylation patterns in 48 children (6-11 years of age), whose mothers were occupationally unexposed or exposed to pesticides early in pregnancy, were determined by Illumina 450 K methylation arrays. RESULTS: A specific methylation profile was observed in prenatally pesticide exposed children carrying the PON1 192R-allele. Differentially methylated genes were enriched in several neuroendocrine signaling pathways including dopamine-DARPP32 feedback (appetite, reward pathways), corticotrophin releasing hormone signaling, nNOS, neuregulin signaling, mTOR signaling, and type II diabetes mellitus signaling. Furthermore, we were able to identify possible candidate genes which mediated the associations between pesticide exposure and increased leptin level, body fat percentage, and difference in BMI Z score between birth and school age. CONCLUSIONS: DNA methylation may be an underlying mechanism explaining an adverse cardio-metabolic health profile in children carrying the PON1 192R-allele and prenatally exposed to pesticides.

Associations between Exposure to Persistent Organic Pollutants in Childhood and Overweight up to 12 Years Later in a Low Exposed Danish Population.

BACKGROUND: Persistent organic pollutants (POPs) have metabolic disrupting abilities and are suggested to contribute to the obesity epidemic. We investigated whether serum concentrations of POPs at 8-10 years of age were associated with subsequent development of overweight at age 14-16 and 20-22 years. METHODS: The study was based on data from the European Youth Heart Study, Danish component (1997). Concentrations of several polychlorinated biphenyls (PCBs) and the organochlorine pesticides p,p-dichlorodiphenyldichloroethylene (DDE) and hexachlorobenzene (HCB) were measured in serum from children aged 8-10 years (n = 509). Information on BMI z-scores, waist circumference and % body fat were collected at clinical examinations at ages 8-10, 14-16 and 20-22 years. Multiple linear regression analyses were performed taking potential confounders into account. RESULTS: Overall, POP serum concentrations were low: median ΣPCB 0.18 µg/g lipid, DDE 0.04 µg/g lipid and HCB 0.03 µg/g lipid. POPs were generally not associated with weight gain at 14-16 and 20-22 years of age, except for an inverse association among the highest exposed girls at 20-22 years of age, which might possibly be explained by multiple testing or residual confounding. CONCLUSION: This study suggests that, in a low exposed population, childhood serum concentrations of PCB, DDE, and HCB are not associated with subsequent weight gain.

Prenatal exposure to persistent organochlorine pollutants is associated with high insulin levels in 5-year-old girls.

BACKGROUND: Several persistent organochlorine pollutants (POPs) possess endocrine disrupting abilities, thereby potentially leading to an increased risk of obesity and metabolic diseases, especially if the exposure occurs during prenatal life. We have previously found associations between prenatal POP exposures and increased BMI, waist circumference and change in BMI from 5 to 7 years of age, though only among girls with overweight mothers. OBJECTIVES: In the same birth cohort, we investigated whether prenatal POP exposure was associated with serum concentrations of insulin and leptin among 5-year-old children, thus possibly mediating the association with overweight and obesity at 7 years of age. METHODS: The analyses were based on a prospective Faroese Birth Cohort (n=656), recruited between 1997 and 2000. Major POPs, polychlorinated biphenyls (PCBs), p,p'-dichlorodiphenyldichloroethylene (DDE) and hexachlorobenzene (HCB), were measured in maternal pregnancy serum and breast milk. Children were followed-up at the age of 5 years where a non-fasting blood sample was drawn; 520 children (273 boys and 247 girls) had adequate serum amounts available for biomarker analyses by Luminex® technology. Insulin and leptin concentrations were transformed from continuous to binary variables, using the 75th percentile as a cut-off point. Multiple logistic regression was used to investigate associations between prenatal POP exposures and non-fasting serum concentrations of insulin and leptin at age 5 while taking into account confounders. RESULTS: Girls with highest prenatal POP exposure were more likely to have high non-fasting insulin levels (PCBs 4th quartile: OR=3.71; 95% CI: 1.36, 10.01. DDE 4th quartile: OR=2.75; 95% CI: 1.09, 6.90. HCB 4th quartile: OR=1.98; 95% CI: 1.06, 3.69) compared to girls in the lowest quartile. No significant associations were observed with leptin, or among boys. A mediating effect of insulin or leptin on later obesity was not observed. CONCLUSION: These findings suggest, that for girls, prenatal exposure to POPs may play a role for later development of metabolic diseases by affecting the level of insulin.

Occupational pesticide exposure in early pregnancy associated with sex-specific neurobehavioral deficits in the children at school age.

Prenatal exposure to pesticides may affect neurodevelopment, while the impact of modern pesticides is unclear. From 1997-2001, women working in greenhouse horticultures were recruited at the beginning of their pregnancy. Based on detailed interview of the women and their employers, those categorized as occupationally exposed to pesticides were moved to unexposed work functions or went on paid leave, while women without any exposure were considered unexposed controls. Of the resulting birth cohort of 203 children, 133 (65%) were examined at age 6 to 11 years together with 44 newly recruited children of same age whose mothers were not occupationally exposed to pesticides in pregnancy. All children underwent a standardized examination including a battery of neurodevelopmental tests. Maternal occupational pesticide exposure in early pregnancy was associated with prolonged brainstem auditory evoked potential latencies in the children as a whole and with impaired neuropsychological function in girls, while no effect was apparent in boys. In girls, language and motor speed functions were significantly inversely associated with prenatal exposure, and a non-significant tendency toward decreased function was also seen for other neuropsychological outcomes. A structural equation model that combined all these test results showed an overall impaired neuropsychological function in girls prenatally exposed to pesticides. Thus, our findings suggest an adverse effect of maternal occupational pesticide exposure on their children's neurodevelopment, despite the fact that the exposures occurred solely during early pregnancy and under well regulated working conditions, where special measures to protect pregnant women were applied.

Association between prenatal polychlorinated biphenyl exposure and obesity development at ages 5 and 7 y: a prospective cohort study of 656 children from the Faroe Islands.

BACKGROUND: Chemicals with endocrine-disrupting abilities may act as obesogens and interfere with the body's natural weight-control mechanisms, especially if exposure occurs during prenatal life. OBJECTIVE: We examined the association between prenatal exposure to polychlorinated biphenyls (PCBs) and p,p'-dichlorodiphenyldichloroethylene (DDE) and subsequent obesity at 5 and 7 y of age. DESIGN: From 1997 to 2000, 656 pregnant Faroese women were recruited. PCB and DDE were measured in maternal serum and breast milk, and children's weight, height, and waist circumference (WC) were measured at clinical examinations at 5 and 7 y of age. The change in body mass index (BMI) from 5 to 7 y of age was calculated. Analyses were performed by using multiple linear regression models for girls and boys separately, taking into account maternal prepregnancy BMI. RESULTS: For 7-y-old girls who had overweight mothers, PCB was associated with increased BMI (ß = 2.07, P = 0.007), and PCB and DDE were associated with an increased change in BMI from 5 to 7 y of age (PCB: ß = 1.23, P = 0.003; DDE: ß = 1.11, P = 0.008). No association was observed with BMI in girls with normal-weight mothers. PCB was associated with increased WC in girls with overweight mothers (ß = 2.48, P = 0.001) and normal-weight mothers (ß = 1.25, P = 0.04); DDE was associated with increased WC only in girls with overweight mothers (ß = 2.21, P = 0.002). No associations were observed between PCB or DDE and BMI in 5-y-old girls. For boys, no associations were observed. CONCLUSIONS: Results suggest that prenatal exposure to PCB and DDE may play a role for subsequent obesity development. Girls whose mothers have a high prepregnancy BMI seem most affected.

Paraoxonase 1 polymorphism and prenatal pesticide exposure associated with adverse cardiovascular risk profiles at school age.

BACKGROUND: Prenatal environmental factors might influence the risk of developing cardiovascular disease later in life. The HDL-associated enzyme paraoxonase 1 (PON1) has anti-oxidative functions that may protect against atherosclerosis. It also hydrolyzes many substrates, including organophosphate pesticides. A common polymorphism, PON1 Q192R, affects both properties, but a potential interaction between PON1 genotype and pesticide exposure on cardiovascular risk factors has not been investigated. We explored if the PON1 Q192R genotype affects cardiovascular risk factors in school-age children prenatally exposed to pesticides. METHODS: Pregnant greenhouse-workers were categorized as high, medium, or not exposed to pesticides. Their children underwent a standardized examination at age 6-to-11 years, where blood pressure, skin folds, and other anthropometric parameters were measured. PON1-genotype was determined for 141 children (88 pesticide exposed and 53 unexposed). Serum was analyzed for insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP3), insulin and leptin. Body fat percentage was calculated from skin fold thicknesses. BMI results were converted to age and sex specific Z-scores. RESULTS: Prenatally pesticide exposed children carrying the PON1 192R-allele had higher abdominal circumference, body fat content, BMI Z-scores, blood pressure, and serum concentrations of leptin and IGF-I at school age than unexposed children. The effects were related to the prenatal exposure level. For children with the PON1 192QQ genotype, none of the variables was affected by prenatal pesticide exposure. CONCLUSION: Our results indicate a gene-environment interaction between prenatal pesticide exposure and the PON1 gene. Only exposed children with the R-allele developed adverse cardiovascular risk profiles thought to be associated with the R-allele.

Lower birth weight and increased body fat at school age in children prenatally exposed to modern pesticides: a prospective study.

BACKGROUND: Endocrine disrupting chemicals have been hypothesized to play a role in the obesity epidemic. Long-term effects of prenatal exposure to non-persistent pesticides on body composition have so far not been investigated. The purpose of this study was to assess possible effects of prenatal exposure to currently used pesticides on children's growth, endocrine and reproductive function. METHODS: In a prospective study of 247 children born by women working in greenhouses in early pregnancy, 168 were categorized as prenatally exposed to pesticides. At three months (n = 203) and at 6 to 11 years of age (n = 177) the children underwent a clinical examination and blood sampling for analysis of IGF-I, IGFBP3 and thyroid hormones. Body fat percentage at age 6 to 11 years was calculated from skin fold measurements. Pesticide related associations were tested by linear multiple regression analysis, adjusting for relevant confounders. RESULTS: Compared to unexposed children birth weight and weight for gestational age were lower in the highly exposed children: -173 g (-322; -23), -4.8% (-9.0; -0.7) and medium exposed children: -139 g (-272; -6), -3.6% (-7.2; -0.0). Exposed (medium and highly together) children had significantly larger increase in BMI Z-score (0.55 SD (95% CI: 0.1; 1.0) from birth to school age) and highly exposed children had 15.8% (0.2; 34.6) larger skin folds and higher body fat percentage compared to unexposed. If prenatally exposed to both pesticides and maternal smoking (any amount), the sum of four skin folds was 46.9% (95% CI: 8.1; 99.5) and body fat percentage 29.1% (95% CI: 3.0; 61.4) higher. There were subtle associations between exposure and TSH Z-score -0.66(-1.287; -0.022) and IGF-I Z-score (girls: -0.62(-1.0; -0.22), boys: 0.38(-0.03; 0.79)), but not IGFBP3. CONCLUSIONS: Occupational exposure to currently used pesticides may have adverse effects in spite of the added protection offered to pregnant women. Maternal exposure to combinations of modern, non-persistent pesticides during early pregnancy was associated with affected growth, both prenatally and postnatally. We found a biphasic association with lower weight at birth followed by increased body fat accumulation from birth to school age. We cannot rule out some residual confounding due to differences in social class, although this was adjusted for. Associations were stronger in highly exposed than in medium exposed children, and effects on body fat content at school age was potentiated by maternal smoking in pregnancy.

Endocrine disrupting effects in vitro of conazole antifungals used as pesticides and pharmaceuticals.

Widely used conazole antifungals were tested for endocrine disruptive effects using a panel of in vitro assays. They all showed endocrine disrupting potential and ability to act via several different mechanisms. Overall the imidazoles (econazole, ketoconazole, miconazole, prochloraz) were more potent than the triazoles (epoxiconazole, propiconazole, tebuconazole). The critical mechanism seems to be disturbance of steroid biosynthesis. In the H295R cell assay, the conazoles decreased the formation of estradiol and testosterone, and increased the concentration of progesterone, indicating inhibition of enzymes involved in the conversion of progesterone to testosterone. Prochloraz was most potent followed by econazole~miconazole>ketoconazole>tebuconazole>epoxiconazole>propiconazole. In the MCF-7 cell proliferation assay, the conazoles showed anti-estrogenic effect, including aromatase inhibition, since they inhibited the response induced by both 17ß-estradiol (miconazole>econazole~ketoconazole>prochloraz>tebuconazole>epoxiconazole>propiconazole) and testosterone (econazole>miconazole>prochloraz>ketoconazole>tebuconazole>epoxiconazole>propiconazole). The triazoles were anti-androgenic in an androgen receptor reporter gene assay (epoxiconazole∼tebuconazole>propiconazole). This effect could not be evaluated for the pharmaceutical imidazoles due to cytotoxicity.

Differences in associations between markers of antioxidative defense and asthma are sex specific.

BACKGROUND: Lungs are exposed to high levels of oxygen, air pollutants, and smoke, all of which stimulate the production of reactive oxygen species (ROS). In addition, inflammatory cells produce ROS, and thus there may be increased demand for antioxidants, including antioxidant enzymes, in inflammatory lung diseases such as asthma. Sex-specific differences have been noted for asthma, which in postpubertal subjects is predominantly found in females. These sex-specific differences may be associated with differences on the molecular level as well. OBJECTIVE: The aim of this cross-sectional study was to examine associations between markers of antioxidative defense and asthma, and to investigate whether these associations were different between women and men. METHODS: Based on the European Community Respiratory Health Survey protocol, subjects were enrolled in a study of asthma risk factors. The multicenter study was conducted in 5 west Danish counties between 2003 and 2006, and the subjects were recruited as a case-enriched random sample of 10,000 Danish inhabitants aged 20 to 44 years selected by their civil registration number. Participants were identified by positive answers to asthma questions on a screening questionnaire, random sampling, or both. Serum selenium concentrations and antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase [GPX], glutathione reductase [GR], and glucose-6-phosphate dehydrogenase [G6PD]) in erythrocytes were measured. Asthma was defined as either current asthma symptoms with bronchial hyperresponsiveness (BHR) or a continuous asthma score based on 8 questions. RESULTS: A total of 1191 mostly white women and men (mean [SD] age, 34.0 [7.1] and 35.1 [7.1] years, respectively) were enrolled in the study. Current asthma symptoms were present in 29.9% (200/670) of women and 22.5% (117/521) of men, with women reporting more positive answers (51.1% vs 40.9%, respectively; P < 0.01) to asthma questions. Serum selenium concentrations were measured in 1151 subjects (640 women, 511 men), and antioxidant enzyme activities were measured in 295 subjects (161 women, 134 men). Women had higher enzyme activities of most antioxidant enzymes (GPX, P = 0.006; GR, P < 0.001; and G6PD, P = 0.009) than did men. Although the serum selenium concentration was inversely associated with asthma in both sexes, there was a female preponderance, with 3.5% lower serum selenium in subjects with current asthma symptoms with BHR (n = 77) compared with controls (n = 287). GR activity was associated with asthma in men, with 5.7% higher enzyme activity in subjects with current asthma symptoms with BHR (n = 14) compared with controls (n = 77). However, a significant interaction with gender was observed for analyses of GR (P = 0.02), but not for analyses of selenium. CONCLUSIONS: In this study of asthma risk factors, women had higher levels of enzyme activities than did men in a randomly selected Danish population, and sex-specific differences were found in the associations between markers of antioxidative defense and asthma.

Impaired reproductive development in sons of women occupationally exposed to pesticides during pregnancy.

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 pesticide-exposed 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.