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      Human anogenital distance: an update on fetal smoke-exposure and integration of the perinatal literature on sex differences

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          Abstract

          STUDY QUESTION

          Do sex and maternal smoking effects on human fetal anogenital distance (AGD) persist in a larger study and how do these data integrate with the wider literature on perinatal human AGD, especially with respect to sex differences?

          SUMMARY ANSWER

          Second trimester sex differences in AGD are broadly consistent with neonatal and infant measures of AGD and maternal cigarette smoking is associated with a temporary increase in male AGD in the absence of changes in circulating testosterone.

          WHAT IS KNOWN ALREADY

          AGD is a biomarker of fetal androgen exposure, a reduced AGD in males being associated with cryptorchidism, hypospadias and reduced penile length. Normative fetal AGD data remain partial and windows of sensitivity of human fetal AGD to disruption are not known.

          STUDY DESIGN, SIZE, DURATION

          The effects of fetal sex and maternal cigarette smoking on the second trimester (11–21 weeks of gestation) human fetal AGD were studied, along with measurement of testosterone and testicular transcripts associated with apoptosis and proliferation.

          PARTICIPANTS/MATERIALS, SETTING METHODS

          AGD, measured from the centre of the anus to the posterior/caudal root of penis/clitoris (AGD app) was determined in 56 female and 70 male morphologically normal fetuses. These data were integrated with current literature on perinatal AGD in humans.

          MAIN RESULTS AND THE ROLE OF CHANCE

          At 11–13 weeks of gestation male fetal AGD app was 61% ( P< 0.001) longer than in females, increasing to 70% at 17–21 weeks. This sexual dimorphism was independent of growth characteristics (fetal weight, length, gonad weight). We confirmed that at 14–16 weeks of gestation male fetal AGD app was increased 28% ( P < 0.05) by in utero cigarette smoke exposure. Testosterone levels were not affected by smoking. To develop normative data, our findings have been integrated with available data from in vivo ultrasound scans and neonatal studies. Inter-study variations in male/female AGD differences lead to the conclusion that normalization and standardization approaches should be developed to enable confidence in comparing data from different perinatal AGD studies.

          LIMITATIONS, REASONS FOR CAUTION

          Sex differences, and a smoking-dependent increase in male fetal AGD at 14–16 weeks, identified in a preliminary study, were confirmed with a larger number of fetuses. However, human fetal AGD should, be re-assessed once much larger numbers of fetuses have been studied and this should be integrated with more detailed analysis of maternal lifestyle. Direct study of human fetal genital tissues is required for further mechanistic insights.

          WIDER IMPLICATIONS OF THE FINDINGS

          Fetal exposure to cigarette smoke chemicals is known to lead to reduced fertility in men and women. Integration of our data into the perinatal human AGD literature shows that more work needs to be done to enable reliable inter-study comparisons.

          STUDY FUNDING/COMPETING INTEREST(S)

          The study was supported by grants from the Chief Scientist Office (Scottish Executive, CZG/1/109 & CZG/4/742), NHS Grampian Endowments (08/02), the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 212885 and the Medical Research Council, UK (MR/L010011/1). The authors declare they have no competing interests, be it financial, personal or professional.

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          Most cited references47

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          AIF deficiency compromises oxidative phosphorylation.

          Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that, after apoptosis induction, translocates to the nucleus where it participates in apoptotic chromatinolysis. Here, we show that human or mouse cells lacking AIF as a result of homologous recombination or small interfering RNA exhibit high lactate production and enhanced dependency on glycolytic ATP generation, due to severe reduction of respiratory chain complex I activity. Although AIF itself is not a part of complex I, AIF-deficient cells exhibit a reduced content of complex I and of its components, pointing to a role of AIF in the biogenesis and/or maintenance of this polyprotein complex. Harlequin mice with reduced AIF expression due to a retroviral insertion into the AIF gene also manifest a reduced oxidative phosphorylation (OXPHOS) in the retina and in the brain, correlating with reduced expression of complex I subunits, retinal degeneration, and neuronal defects. Altogether, these data point to a role of AIF in OXPHOS and emphasize the dual role of AIF in life and death.
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            First trimester phthalate exposure and anogenital distance in newborns.

            Is first trimester phthalate exposure associated with anogenital distance (AGD), a biomarker of prenatal androgen exposure, in newborns? Concentrations of diethylhexyl phthalate (DEHP) metabolites in first trimester maternal urine samples are inversely associated with AGD in male, but not female, newborns. AGD is a sexually dimorphic measure reflecting prenatal androgen exposure. Prenatal phthalate exposure has been associated with shorter male AGD in multiple animal studies. Prior human studies, which have been limited by small sample size and imprecise timing of exposure and/or outcome, have reported conflicting results. The Infant Development and the Environment Study (TIDES) is a prospective cohort study of pregnant women recruited in prenatal clinics in San Francisco, CA, Minneapolis, MN, Rochester, NY and Seattle, WA in 2010-2012. Participants delivered 787 infants; 753 with complete data are included in this analysis. Any woman over 18 years old who was able to read and write English (or Spanish in CA), who was <13 weeks pregnant, whose pregnancy was not medically threatened and who planned to deliver in a study hospital was eligible to participate. Analyses include all infants whose mothers provided a first trimester urine sample and who were examined at or shortly after birth. Specific gravity (SpG) adjusted concentrations of phthalate metabolites in first trimester urine samples were examined in relation to genital measurements. In boys (N = 366), we obtained two measures of anogenital distance (AGD) (anoscrotal distance, or AGDAS and anopenile distance, AGDAP) as well as penile width (PW). In girls (N = 373), we measured anofourchette distance (AGDAF) and anoclitoral distance (AGDAC). We used multivariable regression models that adjusted for the infant's age at exam, gestational age, weight-for-length Z-score, time of day of urine collection, maternal age and study center. Three metabolites of DEHP were significantly and inversely associated with both measures of boys' AGD. Associations (β, 95% confidence interval (CI)) between AGDAS and (log10) SpG-adjusted phthalate concentrations were: -1.12 (-2.16, -0.07) for mono-2-ethylhexyl phthalate (MEHP), -1.43, (-2.49, -0.38) for mono-2-ethyl-5-oxohexyl phthalate (MEOHP), and -1.28 (-2.29, -0.27) for mono-2-ethyl-5-hydroxyhexyl (MEHHP). Associations were of similar magnitude for AGDAP. Associations were weaker and not statistically significant for PW. No other phthalate metabolites were associated with any genital measurement in boys. No phthalate metabolites were associated with either AGD measure in girls. Exposure assessment was based on a single first trimester urine sample, which may have introduced exposure misclassification. In addition, significant between-center differences suggest that this measurement is difficult to standardize. Our findings are consistent with multiple rodent studies and most human studies which were far smaller. The data we report here suggest that even at current low levels, environmental exposure to DEHP can adversely affect male genital development resulting in reproductive tract changes that may impact reproductive health later in life. These findings have important implications for public policy since most pregnant women are exposed to this ubiquitous chemical. Funding for TIDES was provided by the following grants from the National Institute of Environmental Health Sciences: R01ES016863-04 and R01 ES016863-02S4. The authors report no conflict of interest. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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              Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat.

              More than half of pregnant women in the Western world report intake of mild analgesics, and some of these drugs have been associated with anti-androgenic effects in animal experiments. Intrauterine exposure to anti-androgens is suspected to contribute to the recent increase in male reproductive problems, and many of the anti-androgenic compounds are like the mild analgesics potent inhibitors of prostaglandin synthesis. Therefore, it appears imperative to further investigate the potential endocrine disrupting properties of mild analgesics. In a prospective birth cohort study, 2297 Danish and Finnish pregnant women completed a questionnaire and 491 of the Danish mothers participated in a telephone interview, reporting on their use of mild analgesics during pregnancy. The testicular position of newborns was assessed by trained paediatricians. In rats, the impact of mild analgesics on anogenital distance (AGD) after intrauterine exposure was examined together with the effect on ex vivo gestational day 14.5 testes. In the Danish birth cohort, the use of mild analgesics was dose-dependently associated with congenital cryptorchidism. In particular, use during the second trimester increased the risk. This risk was further increased after the simultaneous use of different analgesics. The association was not found in the Finnish birth cohort. Intrauterine exposure of rats to paracetamol led to a reduction in the AGD and mild analgesics accordingly reduced testosterone production in ex vivo fetal rat testes. There was an association between the timing and the duration of mild analgesic use during pregnancy and the risk of cryptorchidism. These findings were supported by anti-androgenic effects in rat models leading to impaired masculinization. Our results suggest that intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders.
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                Author and article information

                Journal
                Hum Reprod
                Hum. Reprod
                humrep
                humrep
                Human Reproduction (Oxford, England)
                Oxford University Press
                0268-1161
                1460-2350
                February 2016
                04 January 2016
                04 January 2016
                : 31
                : 2
                : 463-472
                Affiliations
                [1 ]Institute of Medical Sciences , University of Aberdeen , Foresterhill, Aberdeen AB25 2ZD, UK
                [2 ]Institute of Applied Health Sciences, University of Aberdeen , Foresterhill, Aberdeen AB25 2ZD, UK
                [3 ]USC INRA 1329 Laboratoire d'Etude des Résidus et Contaminants dans les Aliments, LUNAM Université, Oniris, Nantes F-44307, France
                [4 ]Endocrinology Unit, Queen's Medical Research Institute , University/BHF Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
                [5 ]Institute of Biodiversity , Animal Health & Comparative Medicine (IBAHCM), College of Medical, Veterinary & Life Sciences, University of Glasgow , Bearsden Rd, Glasgow G61 1QH, UK
                Author notes
                [* ]Correspondence address. Tel: +44-1224-437528; Fax: +44-1224-437465; E-mail: p.a.fowler@ 123456abdn.ac.uk
                Article
                dev323
                10.1093/humrep/dev323
                4716811
                26732622
                68e621f1-f700-4343-8a40-2dea92ecb4ad
                © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 24 May 2015
                : 14 November 2015
                : 20 November 2015
                Funding
                Funded by: Chief Scientist Office http://dx.doi.org/10.13039/501100000589
                Award ID: CZG/1/109
                Award ID: CZG/4/742
                Funded by: NHS Grampian Endowments
                Award ID: 08/02
                Funded by: European Community's Seventh Framework Programme
                Award ID: FP7/2007-2013
                Award ID: 212885
                Funded by: Medical Research Council http://dx.doi.org/10.13039/501100000265
                Award ID: MR/L010011/1
                Categories
                Original Articles
                Reproductive Endocrinology

                Human biology
                anogenital distance,endocrine-disrupting chemicals,maternal cigarette smoking human,fetus,normative data,proliferation,apoptosis,second trimester,dysregulation,testosterone

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