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Meeting Report: Measuring Endocrine-Sensitive Endpoints within the First Years of Life

Biostatistics and Epidemiology Division, Health Canada, Ottawa, Ontario, Canada.
Environmental Health Perspectives (Impact Factor: 7.03). 07/2008; 116(7):948-51. DOI: 10.1289/ehp.11226
Source: PubMed

ABSTRACT An international workshop titled "Assessing Endocrine-Related Endpoints within the First Years of Life" was held 30 April-1 May 2007, in Ottawa, Ontario, Canada. Representatives from a number of pregnancy cohort studies in North America and Europe presented options for measuring various endocrine-sensitive endpoints in early life and discussed issues related to performing and using those measures. The workshop focused on measuring reproductive tract developmental endpoints [e.g., anogenital distance (AGD)], endocrine status, and infant anthropometry. To the extent possible, workshop participants strove to develop or recommend standardized measurements that would allow comparisons and pooling of data across studies. The recommended outcomes include thigh fat fold, breast size, vaginal cytology, AGD, location of the testis, testicular size, and growth of the penis, with most of the discussion focusing on the genital exam. Although a number of outcome measures recommended during the genital exam have been associated with exposure to endocrine-disrupting chemicals, little is known about how predictive these effects are of later reproductive health or other chronic health conditions.

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    • "This is supported by several animal studies (Dean et al. 2012; van den Driesche et al. 2012). Measurement of anogenital distance (AGD) has been proposed as a quantitative biomarker of fetal endocrine disruptor exposure in humans (Arbuckle et al. 2008). AGD is a marker of perineal growth and caudal migration of the genital tubercle, and is androgen dependent in male rodents (Bowman et al. 2003). "
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    ABSTRACT: Anogenital distance (AGD) in animals is a sensitive biomarker of fetal endocrine disruption and the associated testicular dysgenesis syndrome (TDS). However, AGD in human infants with cryptorchidism and hypospadias, which are potential manifestations of TDS during childhood, is not clearly described. Our aim was to compare AGD in boys with cryptorchidism or hypospadias against normative data. Boys with isolated cryptorchidism (n = 71, age 13.4 ± 5.8 months) or hypospadias (n = 81, age 11.4 ± 6.2 months) were recruited from a tertiary centre for measurement of AGD and penile length; they were compared to 487 healthy full-term boys from a birth cohort by deriving age-specific standard deviation scores (SDS). Boys with cryptorchidism were older (p = 0.048) compared to boys with hypospadias. Boys with hypospadias had shorter mean AGD and penile length SDS than healthy boys (both p < 0.0001). Mean AGD and penile length SDS values in boys with cryptorchidism were longer than mean values in boys with hypospadias (both p < 0.01) and shorter than mean values in healthy boys (both p < 0.0001). Mean penile length SDS decreased as the severity of hypospadias increased (ptrend = 0.078). In the study population, AGD and penile length were reduced in boys with hypospadias or cryptorchidism relative to normative data derived from a longitudinal birth cohort. The findings support the use of AGD as a quantitative biomarker to examine the prenatal effects of exposure to endocrine disruptors on the development of the male reproductive tract.
    Environmental Health Perspectives 12/2013; 122(2). DOI:10.1289/ehp.1307178 · 7.03 Impact Factor
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    • "Cryptorchidism has been considered as a milder form of TDS while hypospadias, azoospermia and testicular germ cell cancer lie at the severe end of the spectrum (Skakkebaek et al., 2001; Sharpe and Skakkebaek, 2008; Main et al., 2009). AGD has been identified as one of the end-points in US Environmental Protection Agency guidelines for reproductive toxicity studies in animals (Arbuckle et al., 2008), and many animal studies have shown that AGD, a marker of androgenization, is significantly shorter in cryptorchid males (Welsh et al., 2008; Drake et al., 2009). "
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    ABSTRACT: Are the anogenital distance (AGD) and stretched penile length (SPL) shorter in human newborn males with cryptorchidism? AGD is significantly shorter in boys with undescended testis (UDT) and this correlation may indicate that both have a common antecedent early in gestation. Animal studies have reported a critical time period during early gestation termed the male programming window (MPW) where androgen deficiency results in reduced AGD and penile length, as well as cryptorchidism and hypospadias. Two pilot human studies have explored this association but these studies were small and heterogeneous with regard to age, race and had selection bias. A prospective descriptive study involving measurement of AGD and SPL at birth in a racially homogenous sample of 1154 consecutive newborns was performed over a period of 6 months. All measurements were taken by a single trained observer (V.J.). All consecutively born male infants at a community hospital were classified as having descended and or UDT. Testicular position in the undescended group was graded as high scrotal, inguinal or non-palpable. AGD (from the centre of anus to the junction of the smooth and rugated skin of scrotum) and SPL were measured. The AGD index (AGDi) was calculated by dividing AGD by cube root of birthweight. Of the 1154 infants examined, 624 were males and 71 had UDT. AGD was significantly shorter in infants with UDT when compared with infants with descended testis (mean ± SD; 2.21 ± 0.36 versus 2.56 ± 0.31 cm; P < 0.001). AGDi was also significantly shorter in infants with UDT (mean ± SD; 1.68 ± 0.27 versus 1.81 ± 0.20 cm/kg(-3); P < 0.001). Significance was maintained even when preterm (P < 0.001) and low birthweight boys (LBW) (P < 0.001) were excluded. SPL was also significantly shorter in infants with UDT (Mean ± SD; 3.08 ± 0.52 versus 3.31 ± 0.38 cm; P < 0.001) but the significance was not maintained when preterm (P = 0.119) and LBW boys (P = 0.666) were excluded. Birthweight, gestational age and length adjusted regression models showed significantly shorter AGD in infants with UDT, but SPL was not different. Infants with higher position of testis appeared to have a shorter AGD and SPL but the correlation did not reach statistical significance. No difference in AGD or SPL was noted between boys with unilateral and bilateral UDT. The present study did not include data pertaining to maternal or newborn health status. Also parental drug exposure or occupational exposures to endocrine-disrupting chemicals was not studied. These may possibly affect genital anthropometric measurements. The study strengthens the hypothesis of existence of MPW in humans. Shorter AGD in cryptorchid infants may reflect the effect of androgen disruption or deficiency during MPW. AGD may be a more reliable non-invasive marker of androgen action during MPW than SPL to predict reproductive outcomes in humans. Supported by Hypospadias Foundation, India. The authors have no conflict of interest to declare.
    Human Reproduction 07/2013; 28(9). DOI:10.1093/humrep/det286 · 4.59 Impact Factor
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    • "These tests might indicate unusual binding affinity of agents that cause certain teratogenic effects or influence reproductive or growth patterns by interactions with the relevant hormonal receptors regulating these physiological processes. " As predicted by SCOGS, in the last 2 decades, scientists have produced a large body of research results on endocrine disrupting chemicals (Arbuckle and others 2008; Woodruff and others 2011; Vandenberg and others 2012). "
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    ABSTRACT: Scientists participating in 2 multistakeholder meetings in 2011 and in other events have identified a number of ways in which the methods the U.S. Food and Drug Administration (FDA) uses to assess the safety of chemicals in human food should be improved and updated. We evaluated whether FDA's current methods, including its decision-making process, are outdated, as alleged by its critics. We examined a 1982 report by the Select Committee on GRAS Substances (SCOGS) that included suggestions to enhance food additive safety. FDA established SCOGS to review the safety of "generally recognized as safe" (GRAS) substances in response to a directive by President Nixon. When evaluating FDA's response to SCOGS' suggestions, we found that many remain unresolved and relevant today. Our analysis demonstrates that in many cases FDA has not kept pace with scientific developments. Although difficult to pinpoint, we concluded that this situation became more significant after 1997, when FDA launched the voluntary GRAS notification program aimed at enticing manufacturers to inform the agency of their own safety decisions. Looking forward, we recommend that the agency convene an unbiased and independent expert workgroup to conduct a comprehensive review of FDA's science and decision making and develop a path to modernize food additives safety assessment. Areas of concern include toxicology test guidelines, tools used to predict health outcomes, conflict of interest in manufacturers' decisions, lack of a reassessment strategy, and lack of a definition of harm.
    Comprehensive Reviews in Food Science and Food Safety 07/2013; 12(4). DOI:10.1111/1541-4337.12020 · 3.54 Impact Factor
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