Genital defects seen in sons of men taking major diabetes drug.

Large study hints that taking metformin before conception could raise risk of birth defects by affecting sperm.

Fetal bisphenol A and ethinylestradiol exposure alters male rat urogenital tract morphology at birth: Confirmation of prior low-dose findings in CLARITY-BPA.

Bisphenol A (BPA) is a contaminant in virtually all Americans. To examine BPA's adverse effects, the FDA-NCTR, NIEHS, and 14 groups of academic scientists formed a consortium: CLARITY-BPA. The purpose of our study was to investigate the effects of a wide range of doses of BPA on fetal development of the NCTR CD-SD male rat urogenital sinus (UGS). Pregnant rats were administered BPA or positive control ethinylestradiol (EE2) daily, via oral gavage, from gestational day 6 through parturition. Tissues were collected on postnatal day 1 and the UGS was analyzed using computer-assisted 3-D reconstruction. Importantly, only low doses of BPA, as well as EE2, significantly changed birth weight and UGS morphology, including an increased size of the colliculus and decreased size of the urethra, consistent with prior reported BPA and EE2 effects. Our findings provide further evidence that BPA mediates nonmonotonic developmental effects on the fetal urogenital sinus.

Potential Interference of Oil Vehicles on Genital Tubercle Development during the Fetal Period in ICR Mice.

Corn oil, sesame oil, and 10% ethanol in corn oil are commonly used as dosing vehicles in toxicology studies. Since these vegetable oils contain bioactive compounds, it is important for toxicology studies to characterize the toxicities of the dosing vehicles themselves. It has been recently proposed that the width of the genital tubercle (GT), the dorsal-ventral length (D-V length) of the GT, and urethral tube closure in mouse fetuses can be used as novel markers for monitoring sexual development in mice. However, how these parameters are influenced by the dosing vehicles themselves remains unclear. Therefore, we evaluated the effects of corn oil, sesame oil, and 10% ethanol in corn oil on GT width, D-V length, and GT morphology in ICR mice. Our results showed that all three vehicles influenced GT width and D-V length, but not GT morphology, suggesting that the effects of dosing vehicles themselves might need to be considered when GT width or D-V length is used as a parameter to evaluate the effects of chemicals on GT development.

High Prenatal Exposure to Bisphenol A Reduces Anogenital Distance in Healthy Male Newborns.

OBJECTIVE: To estimate the relationship between cord blood bisphenol A (BPA) levels and anogenital measurements in healthy newborns. METHODS: Pregnancy and birth history, together with body mass and length data, anogenital measurements, penile measurements and cord blood samples were obtained from healthy newborns. Cord blood concentration of BPA was analyzed by sandwich enzyme-linked immunosorbent assays kit. RESULTS: Among 130 healthy newborns (72 boys, 58 girls), mean anopenile distance was 45.2±6 mm and anoscrotal distance was 21.9±5.4 mm in boys; mean anoclitoral distance was 33.8±6.6 mm and mean anofourchette distance was 12.2±4.9 mm in girls. Mean cord blood BPA level was 4.75±2.18 ng/mL. 90th percentile value for cord blood BPA was 8.26 ng/mL and the analysis showed a statistically significant correlation between anoscrotal distance and cord blood BPA levels above the 90th percentile (p=0.047) in boys. The changes in anogenital distance in girls were not statistically significant. CONCLUSION: We showed a significant association between high cord blood BPA levels and shortened anoscrotal distance in male newborns. However, this result should be interpreted with caution since there were no significant external genital abnormalities in our study group.

Assessing the impact of in-utero exposures: potential effects of paracetamol on male reproductive development.

Human male reproductive disorders (cryptorchidism, hypospadias, testicular cancer and low sperm counts) are common and some may be increasing in incidence worldwide. These associated disorders can arise from subnormal testosterone production during fetal life. This has resulted in a focus on in-utero environmental influences that may result in reproductive effects on the offspring in later life. Over recent years, there has been a dramatic increase in the scientific literature describing associations between in-utero environmental exposures (eg, industrial chemicals and pharmaceuticals) and subsequent reproductive outcomes in male offspring. This includes studies investigating a potential role for in-utero analgesic exposure(s) on the fetal testis; however, providing definitive evidence of such effects presents numerous challenges. In this review, we describe an approach to assessing the potential clinical relevance of in-utero (and postnatal) environmental exposures on subsequent male reproductive function using exposure to the analgesic paracetamol as an example.

Comparing effect levels of regulatory studies with endpoints derived in targeted anti-androgenic studies: example prochloraz.

Prochloraz is an imidazole fungicide, and its regulatory toxicological data package has been primarily generated in the 1990s. More recently, studies have been published demonstrating an interaction with hormone receptors/steroidogenesis and effects with an endocrine mode of action. In the present study, prochloraz has been investigated in a comprehensive in vivo study including relevant elements of current regulatory reproduction toxicity studies and additional mechanistic parameters. Prochloraz was administered per gavage in oil from GD 6 to PND 83 to pregnant and lactating Wistar rats and their respective offspring, at doses of 0.01 mg/kg bw/day (acceptable daily intake of prochloraz), 5 mg/kg bw/day [expected no-observed-effect-level (NOEL)] and 30 mg/kg bw/day. At 30 mg/kg bw/day maternal and offspring effects (decreased viability, lower number of live offspring) were seen including a delayed entry into male puberty (+1 day) accompanied by lower male offspring body weights, increased anogenital distance/index in females and transiently retained nipples in males at PND 12 (not seen at PND 20). The only finding at the "expected NOEL" was increased incidences of transiently retained nipples in males which are not considered adverse. No effects were seen in the low-dose group. There was no evidence for a non-monotonic dose-response curve or effects at low levels.

First trimester phthalate exposure and male newborn genital anomalies.

BACKGROUND: Anti-androgenic phthalates are environmental chemicals that affect male genital development in rodents leading to genitourinary birth defects. We examined whether first trimester phthalate exposure may exert similar effects in humans leading to an increased incidence of newborn male genital anomalies in a multi-center cohort study. METHODS: We recruited first trimester pregnant women within The Infant Development and the Environment Study (TIDES) from 2010 to 2012 from four study centers and limited analyses to all mother/male infant dyads who had complete urinary phthalate and birth exam data (N=371). We used multivariate logistic regression to determine the odds of having a genital anomaly in relation to phthalate exposure. RESULTS: Hydrocele was the primary abnormality observed in the cohort (N=30) followed by undescended testes (N=5) and hypospadias (N=3). We observed a statistically significant 2.5 fold increased risk (95% CI 1.1, 5.9) of having any anomaly and 3.0 fold increased risk (95% CI 1.2, 7.6) of isolated hydrocele in relation to a one log unit increase in the sum of di-ethylhexyl phthalate (DEHP) metabolites. CONCLUSIONS: First trimester urinary DEHP metabolite concentrations were associated with increased odds of any newborn genital anomaly, and this association was primarily driven by isolated hydrocele which made up the majority of anomalies in newborn males. The association with hydrocele has not been previously reported and suggests that it may be an endpoint affected by prenatal phthalate exposures in the first trimester of development. Future human studies should include hydrocele assessment in order to confirm findings.

Dichlorodiphenyltrichloroethane exposure and anogenital distance in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) birth cohort study, South Africa.

Dichlorodiphenyltrichloroethane (DDT) is used for malaria control by 10 countries, nine of which are in Africa. Technical DDT contains various isomers with 65-80% insecticidal p,p'-DDT and 15-21% o,p'-DDT, an estrogenic chemical, while the persistent metabolite of p,p'-DDT, dichlorodiphenyldichloroethylene (p,p'-DDE), is an antiandrogen. In utero antiandrogenic exposure reduces anogenital distance in animal models and the anal position index in a single study. This study examined the associations between mother's serum DDT and DDE levels at delivery and anogenital distance in their children at birth and age 1 year. Data were collected as part of the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE), a birth cohort study located in rural South Africa. DDT and DDE concentrations were measured in blood samples collected from 752 mothers at delivery. Anogenital distance measurements, taken at birth (n = 671) and age 1 year (n = 674), included anofourchette and anoclitoral distances in girls, and anoscrotal and anopenile lengths in boys. We also measured anococcygeal and coccyx-fourchette distances in girls, while in boys, we measured anococcygeal and coccyx-scrotal distances as well as penile length and penile width. The anal position index is calculated for both sexes as anoscrotal/coccyx-scrotal in boys and anofourchette/coccyx-fourchette in girls. We found no associations between p,p'-DDT/-DDE or o,p'-DDT and anogenital distance measurements at birth in either boys or girls. At 1 year, o,p'-DDE was negatively associated with anofourchette in girls (ß =-1.32 mm, 95% confidence interval (CI) = -2.27, -0.38) and positively associated with penile width in boys (ß = 0.30 mm, 95% CI = 0.00, 0.60). The results do not suggest an overt antiandrogenic or estrogenic effect on anogenital distance after long-term DDT exposure. These weak associations may be due to chance.

Severity of birth defects after propylthiouracil exposure in early pregnancy.

BACKGROUND: Propylthiouracil (PTU) used in the treatment of maternal hyperthyroidism in early pregnancy may be associated with a higher prevalence of birth defects in the face and neck region and in the urinary system but the severity of these complications remains to be elucidated. METHODS: Review of hospital-registered cases of birth defects in the face and neck region and in the urinary system after PTU exposure in early pregnancy. We obtained information on maternal redeemed prescription of PTU and child diagnosis of birth defect from nationwide registers for all children born in Denmark between 1996 and 2008 (n=817,093). The children were followed until December 31, 2010 (median age, 8.3 years) and the Cox proportional hazards model was used to estimate adjusted hazard ratio (HR) with 95% confidence interval (CI) for having a birth defect after PTU exposure versus nonexposed children (n=811,730). RESULTS: Fourteen cases of birth defects were identified in the face and neck region and in the urinary system after PTU exposure in early pregnancy; 11 children were exposed to PTU only (n=564), whereas 3 children were born to mothers who switched from methimazole (MMI)/carbimazole (CMZ) to PTU in early pregnancy (n=159). Among children exposed to PTU only, the adjusted HR for having a birth defect in the face and neck region was 4.92 (95% CI 2.04-11.86) and in the urinary system 2.73 (1.22-6.07). Looking into details of the 14 cases, 7 children were diagnosed with a birth defect in the face and neck region (preauricular and branchial sinus/fistula/cyst) and 7 children had a birth defect in the urinary system (single cyst of kidney and hydronephrosis). Surgical treatment was registered in 6 of the cases with a birth defect in the face and neck region and 3 of the cases with a birth defect in the urinary system. Two of the children with a birth defect in the urinary system also had other birth defects (genital organs). CONCLUSIONS: We report details on possible PTU-associated birth defects. They tend to be less severe than the defects observed after MMI/CMZ exposure. Yet, the majority of affected children had to undergo surgery.

Perinatal androgenic exposure and reproductive health effects female rat offspring.

Environmental contaminants known as endocrine-disrupting chemicals (EDC) have been associated with adverse effects on reproductive processes. These chemicals may mimic or antagonize endogenous hormones, disrupting reproductive functions. Although preliminary studies focused on environmental estrogens, the presence of compounds with androgenic activity has also been described. This study examines exposure of female pregnant and lactating rats to low doses of androgens and assesses potential effects on female offspring. Pregnant Wistar rats were exposed to testosterone propionate (TP) at doses of 0.05, 0.1, or 0.2 mg/kg or corn oil (vehicle), subcutaneously, to determine influence on reproductive health of female offspring. There were two exposure groups: (1) rats treated from gestational day (GD) 12 until GD 20; and (2) animals treated from GD 12 until the end of lactation. Perinatal exposure to TP produced increased anogenital distance after birth and diminished height of uterine glandular epithelium at puberty in animals exposed to 0.2 mg/kg. However, these alterations were not sufficient to impair sexual differentiation and normal physiology of the female rat reproductive tract.

Risk of congenital anomalies in relation to the uptake of trihalomethane from drinking water during pregnancy.

OBJECTIVES: Congenital anomalies have been inconsistently associated with maternal crude estimated exposure to drinking water trihalomethane (THM). We investigated the relationship between individual THM uptake during the first trimester of pregnancy and congenital anomalies. METHODS: We estimated maternal THM uptake for 3074 live births using residential tap water concentrations, drinking water ingestion, showering and bathing, and uptake factors of THM in the blood. Multiple logistic regression was used to investigate the association of THM exposure with congenital anomalies. RESULTS: We observed no statistically significant relationships between congenital anomalies and the total THM internal dose. We found little indication of a dose-response relationship for brominated THM and congenital heart anomalies. The relationship was statistically significant for bromodichloromethane (BDCM) (OR=2.16, 95% CI 1.05 to 4.46, highest vs lowest tertile) during the first month of pregnancy. During the first trimester of pregnancy, the probability of developing heart anomalies increased for every 0.1 µg/d increase in the BDCM and for every 0.01 µg/d increase in the internal dibromochloromethane (DBCM) dose (OR 1.70, 95% CI 1.09 to 2.66, and OR 1.25, 95% CI 1.01 to 1.54, respectively). A dose-response relationship was evident for musculoskeletal anomalies and DBCM exposure during the first and second months of pregnancy, while BDCM exposure tended to increase the risk of urogenital anomalies. CONCLUSIONS: This study shows some evidence for an association between the internal dose of THM and the risk of congenital anomalies. In particular, increased prenatal exposure to brominated THM might increase the risk of congenital heart and musculoskeletal anomalies.

The influence of endocrine disruptors on growth and development of children.

PURPOSE OF REVIEW: This review describes the most recent data about the effects of endocrine disrupting compounds (EDCs) on infant and early childhood growth and reproductive tract development as well as controversies in the field. RECENT FINDINGS: EDCs are present in pregnant women, young children and adolescents. Whether the level of exposure contributes to disease is an ongoing debate. Epidemiological studies suggest associations between prenatal EDC exposure and disease outcome, but animal studies using controlled EDC exposure have varying results with underlying mechanisms largely unknown. SUMMARY: Human exposure to EDCs is widespread; bisphenol A, phthalates and persistent organic pollutants are detectable in all age groups and geographical locations in the USA. Epidemiological and animal studies suggest that phthalates and bisphenol A have adverse effects on birth weight, promote development of childhood obesity and adversely affect male reproductive tract development. Differences in the interpretation of available studies underlie the disparate conclusions of scientific and regulatory body's panels on potential toxicological effects of EDCs at current levels of human exposure.

Environmental pollutants and diseases of sexual development in humans and wildlife in South Africa: harbingers of impact on overall health?

This study deals with disorders of sexual development in humans, wildlife and animals in an urban nature reserve (RNR) and a currently DDT-sprayed malarial area. High levels of oestrogenic chemical residues in water, sediment and tissue; skewed sex ratios; reduced biodiversity; gonadal malformations in sharptooth catfish and freshwater snails; intersex in catfish; and impaired spermatogenesis in catfish and striped mouse are of serious concern in the RNR. Persistent eggshell thinning in African darter eggs, intersex in male Mozambican tilapia, follicular atresia in females and impaired spermatogenesis in males following laboratory exposure of parent fish to environmentally relevant DDT and DDE concentrations, and abnormalities in freshwater snails were found in the DDT-sprayed area. Human studies related to DDT exposure indicated impaired semen quality, a weak association with sperm chromatin defects and higher risks for external urogenital birth defects in those who were born to mothers whose houses were sprayed and those who were homemakers (stay at home mother) instead of being employed. These findings indicate that diseases of sexual development occurred in both human and wildlife populations exposed to environmental endocrine disruptor chemicals in South Africa. The chemical mixtures, possibly related to disorders of sexual differentiation (DSD), were very different between the two. However, DSD occurred concurrently in the malarial area, possibly indicating that humans and wildlife shared exposures. Moreover, it emphasizes the importance of suspecting disease in the other when disease is found in either human or wildlife populations.

Exposure to environmental endocrine disruptors and child development.

Exposure to exogenous chemicals can affect endocrine function at multiple sites and through numerous specific modes of action, which may have far-reaching effects on human health and development. Widespread human exposure to known or suspected endocrine disrupting chemicals (EDCs) has been documented in the United States and worldwide, as have trends for increased rates of endocrine-related diseases and disorders among children. While human epidemiology studies of exposure to EDCs and children's health remain extremely limited, a growing body of evidence shows that exposure to a number of chemicals commonly found in consumer goods, personal care products, food, drinking water, and other sources may adversely affect child development through altered endocrine function. This narrative review provides a brief introduction to several common EDCs (with a specific focus on persistent organic pollutants, phthalates, bisphenol A, and contemporary-use pesticides, which represent only a small number of all known or suspected EDCs), an overview of the state of the human evidence for adverse effects of EDCs on child development (fetal growth, early reproductive tract development, pubertal development, neurodevelopment, and obesity), guidance for health care providers based on current knowledge, and recommendations for future research.

Corticosteroid-induced kidney dysmorphogenesis is associated with deregulated expression of known cystogenic molecules, as well as Indian hedgehog.

An intact genome is essential for kidney growth and differentiation, but less is known about whether, and how, an altered fetal milieu modifies these processes. Maternal low-protein diets perturb growth of the metanephros, the precursor of the mature kidney. Fetal corticosteroid overexposure may, in part, mediate this, because such diets downregulate placental 11beta-hydroxysteroid dehydrogenase-2, which degrades maternal corticosteroids. We report that glucocorticoid and mineralocorticoid receptors are expressed in mouse metanephric epithelia. Metanephroi maintained in organ culture with hydrocortisone (1.4 or 14 microM) underwent a dose-dependant deceleration of overall growth accompanied by cyst formation. Dexamethasone, a glucocorticoid, reproduced these outcomes, but aldosterone, a mineralocorticoid, did not. Hydrocortisone upregulated transcripts levels of cadherin-11 and downregulated prospero-related homeobox-1, hence mimicking reported effects of maternal low-protein diet. Hydrocortisone also upregulated transcripts encoding Na(+)-K(+)-ATPase subunits and ligands for the epidermal growth factor receptor, all previously implicated in renal cyst growth. The most upregulated transcript, however, was indian hedgehog, and the encoded protein was immunodetected in metanephric cysts. Furthermore, in the presence of hydrocortisone, cystogenesis, but not whole organ growth, was significantly reduced by cyclopamine, a drug downregulating hedgehog signaling. Finally, both glucocorticoid receptor and indian hedgehog proteins were detected by immunohistochemistry in cystic tubules within human dysplastic kidneys, consistent with the hypothesis that these molecules modify the severity of this congenital malformation. Collectively, our observations raise the possibility that enhanced hedgehog signaling is an important stimulus for renal cyst formation. Furthermore, pharmacological inhibition of this pathway should be explored as a potential therapy for renal cystic diseases, starting with relevant animal models.