Decrease in anogenital distance among male infants with prenatal phthalate exposure
01 Aug 2005-Environmental Health Perspectives (National Institute of Environmental Health Sciences)-Vol. 113, Iss: 8, pp 1056-1061
TL;DR: The hypothesis that prenatal phthalate exposure at environmental levels can adversely affect male reproductive development in humans is supported.
Abstract: Prenatal phthalate exposure impairs testicular function and shortens anogenital distance (AGD) in male rodents. We present data from the first study to examine AGD and other genital measurements in relation to prenatal phthalate exposure in humans. A standardized measure of AGD was obtained in 134 boys 2–36 months of age. AGD was significantly correlated with penile volume (R = 0.27, p = 0.001) and the proportion of boys with incomplete testicular descent (R = 0.20, p = 0.02). We defined the anogenital index (AGI) as AGD divided by weight at examination [AGI = AGD/weight (mm/kg)] and calculated the age-adjusted AGI by regression analysis. We examined nine phthalate monoester metabolites, measured in prenatal urine samples, as predictors of age-adjusted AGI in regression and categorical analyses that included all participants with prenatal urine samples (n = 85). Urinary concentrations of four phthalate metabolites [monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), and monoisobutyl phthalate (MiBP)] were inversely related to AGI. After adjusting for age at examination, p-values for regression coefficients ranged from 0.007 to 0.097. Comparing boys with prenatal MBP concentration in the highest quartile with those in the lowest quartile, the odds ratio for a shorter than expected AGI was 10.2 (95% confidence interval, 2.5 to 42.2). The corresponding odds ratios for MEP, MBzP, and MiBP were 4.7, 3.8, and 9.1, respectively (all p-values < 0.05). We defined a summary phthalate score to quantify joint exposure to these four phthalate metabolites. The age-adjusted AGI decreased significantly with increasing phthalate score (p-value for slope = 0.009). The associations between male genital development and phthalate exposure seen here are consistent with the phthalate-related syndrome of incomplete virilization that has been reported in prenatally exposed rodents. The median concentrations of phthalate metabolites that are associated with short AGI and incomplete testicular descent are below those found in one-quarter of the female population of the United States, based on a nationwide sample. These data support the hypothesis that prenatal phthalate exposure at environmental levels can adversely affect male reproductive development in humans.
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TL;DR: The evidence that endocrine disruptors have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology is presented.
Abstract: Thereisgrowinginterestinthepossiblehealththreatposedbyendocrine-disruptingchemicals (EDCs), which are substances in our environment, food, and consumer products that interfere with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction. In this first Scientific Statement of The Endocrine Society, we present the evidence that endocrine disruptors have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology. Results from animal models, human clinical observations, and epidemiological studies converge to implicate EDCs as a significant concern to public health. The mechanisms of EDCs involve divergent pathways including (but not limited to) estrogenic, antiandrogenic, thyroid, peroxisome proliferator-activated receptor , retinoid, and actions through other nuclear receptors; steroidogenic enzymes; neurotransmitter receptors and systems; and many other pathways that are highly conserved in wildlife and humans, and which can be modeled in laboratory in vitro and in vivo models. Furthermore, EDCs represent a broad class of molecules such as organochlorinated pesticides and industrial chemicals, plastics and plasticizers, fuels, and many other chemicals that are present in the environment or are in widespread use. We make a number of recommendations to increase understanding of effects of EDCs, including enhancing increased basic and clinical research, invoking the precautionary principle, and advocating involvement of individual and scientific society stakeholders in communicating and implementing changes in public policy and awareness. (Endocrine Reviews 30: 293–342, 2009)
3,576 citations
Cites background from "Decrease in anogenital distance amo..."
...In the rodent, however, aTDS-like conditioncan be observed after fetal exposure to phthalates (20), and the reduced anogenital distance observed in the rat (22) was observedinarecentepidemiological studyonhumanmalenewborns (23)....
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...DES Fetal rats: hypospadias, cryptorchidism, micropenis, increased transmitted susceptibility to malignancies (28) Hypospadias, cryptorchidism, micropenis, epididymal cysts (28) Increased ER expression in epididymis (43) Reduced insulin-like factor 3 (465) DDT Adult rats: decreased fertility (466) Cryptorchidism DDE Cryptorchidism Phthalates Reduced anogenital distance (22) Reduced anogenital distance (23) and Leydig cell function, hypospadias Decreased testosterone synthesis (468) Cryptorchidism (467) Cryptorchidism (14, 20) Oligospermia Reduced fertility (14, 20) PCBs Fetal rat: decreased spermatogenesis, delayed puberty Reduced penile length, delayed sexual maturation, reduced fertility Fetal: testis cancer BPA Increased prostate size (469) Aberrant development of prostate and urethra (470) Prostate cancer (122) Increased anogenital distanceAltered periductal stroma in the prostate (471) Increased ER expression in hypothalamus (42) Increased AR expression in prostate (469) 298 Diamanti-Kandarakis et al....
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...(23) determined “anogenital index” (anogenital distance/body weight) and testicular position in young boys (mean age, 16 months) and corresponding maternal levels of urinary phthalate metabolites at three separate clinical sites....
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TL;DR: It is concluded that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses, and fundamental changes in chemical testing and safety determination are needed to protect human health.
Abstract: For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from...
2,475 citations
TL;DR: Current understanding of the benefits and concerns surrounding the use of plastics are synthesized, and future priorities, challenges and opportunities are looked to.
Abstract: Plastics have transformed everyday life; usage is increasing and annual production is likely to exceed 300 million tonnes by 2010. In this concluding paper to the Theme Issue on Plastics, the Environment and Human Health, we synthesize current understanding of the benefits and concerns surrounding the use of plastics and look to future priorities, challenges and opportunities. It is evident that plastics bring many societal benefits and offer future technological and medical advances. However, concerns about usage and disposal are diverse and include accumulation of waste in landfills and in natural habitats, physical problems for wildlife resulting from ingestion or entanglement in plastic, the leaching of chemicals from plastic products and the potential for plastics to transfer chemicals to wildlife and humans. However, perhaps the most important overriding concern, which is implicit throughout this volume, is that our current usage is not sustainable. Around 4 per cent of world oil production is used as a feedstock to make plastics and a similar amount is used as energy in the process. Yet over a third of current production is used to make items of packaging, which are then rapidly discarded. Given our declining reserves of fossil fuels, and finite capacity for disposal of waste to landfill, this linear use of hydrocarbons, via packaging and other short-lived applications of plastic, is simply not sustainable. There are solutions, including material reduction, design for end-of-life recyclability, increased recycling capacity, development of bio-based feedstocks, strategies to reduce littering, the application of green chemistry life-cycle analyses and revised risk assessment approaches. Such measures will be most effective through the combined actions of the public, industry, scientists and policymakers. There is some urgency, as the quantity of plastics produced in the first 10 years of the current century is likely to approach the quantity produced in the entire century that preceded.
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TL;DR: The growing human literature correlating environmental BPA exposure to adverse effects in humans, along with laboratory studies in many species including primates, provides increasing support that environmental B PA exposure can be harmful to humans, especially in regards to behavioral and other effects in children.
1,438 citations
Cites background from "Decrease in anogenital distance amo..."
...Similarly, shorter adjusted AGD may indicate antiandrogenic exposures during embryonic development in humans [99], and the current study indicates that the relative AGD may persist through childhood and the post-pubertal period [94], although more studies need to be done to verify this endpoint in humans....
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TL;DR: This paper presents an overview on current risk assessments done by expert panels as well as on exposure assessment data, based on ambient and on current human biomonitoring results, that prove that the tolerable intake of children is exceeded to a considerable degree.
1,212 citations
References
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TL;DR: In this article, the average concentration of a particular contaminant during some period of time, a certain proportion of the collected samples is often reported to be below the limit of detection.
Abstract: In the attempt to estimate the average concentration of a particular contaminant during some period of time, a certain proportion of the collected samples is often reported to be below the limit of detection. The statistical terminology for these results is known as censored data, i.e., nonzero values which cannot be measured but are known to be below some threshold. Samples taken over time are assumed to follow a lognormal distribution. Given this assumption, several techniques are presented for estimation of the average concentration from data containing nondetectable values. The techniques proposed include three methods of estimation with a left-censored lognormal distribution: a maximum likelihood statistical method and two methods involving the limit of detection. Each method is evaluated using computer simulation with respect to the bias associated with estimation of the mean and standard deviation. The maximum likelihood method was shown to produce unbiased estimates of both the mean and s...
2,670 citations
TL;DR: Existing evidence supporting a new concept that poor semen quality, testis cancer, undescended testis and hypospadias are symptoms of one underlying entity, the testicular dysgenesis syndrome (TDS), which may be increasingly common due to adverse environmental influences is summarized.
Abstract: Numerous reports have recently focused on various aspects of adverse trends in male reproductive health, such as the rising incidence of testicular cancer; low and probably declining semen quality; high and possibly increasing frequencies of undescended testis and hypospadias; and an apparently growing demand for assisted reproduction. Due to specialization in medicine and different ages at presentation of symptoms, reproductive problems used to be analysed separately by various professional groups, e.g. paediatric endocrinologists, urologists, andrologists and oncologists. This article summarizes existing evidence supporting a new concept that poor semen quality, testis cancer, undescended testis and hypospadias are symptoms of one underlying entity, the testicular dysgenesis syndrome (TDS), which may be increasingly common due to adverse environmental influences. Experimental and epidemiological studies suggest that TDS is a result of disruption of embryonal programming and gonadal development during fetal life. Therefore, we recommend that future epidemiological studies on trends in male reproductive health should not focus on one symptom only, but be more comprehensive and take all aspects of TDS into account. Otherwise, important biological information may be lost.
2,096 citations
"Decrease in anogenital distance amo..." refers background in this paper
...It has recently been suggested (Fisher 2004) that this “phthalate syndrome” shares many features with the human testicular dysgenesis syndrome proposed by Skakkebaek et al. (2001) to follow chemically induced disruption of embryonic programming and gonadal development during fetal life....
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TL;DR: It is hypothesized that the phthalate esters that altered testis function in the pubertal male rat would also alter testisfunction in the fetal male and produce malformations of androgen-dependent tissues and, in summary, DEHP, BBP, and DINP all altered sexual differentiation, whereas DOTP, DEP, or DMP were ineffective at this dose.
1,020 citations
TL;DR: For example, this article measured the urinary monoester metabolites of seven commonly used phthalates in approximately 2,540 samples collected from participants of the National Health and Nutrition Examination Survey (NHANES), 1999-2000, who were greater than or equal to 6 years of age.
Abstract: We measured the urinary monoester metabolites of seven commonly used phthalates in approximately 2,540 samples collected from participants of the National Health and Nutrition Examination Survey (NHANES), 1999-2000, who were greater than or equal to 6 years of age. We found detectable levels of metabolites monoethyl phthalate (MEP), monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), and mono-(2-ethylhexyl) phthalate (MEHP) in > 75% of the samples, suggesting widespread exposure in the United States to diethyl phthalate, dibutyl phthalate or diisobutylphthalate, benzylbutyl phthalate, and di-(2-ethylhexyl) phthalate, respectively. We infrequently detected monoisononyl phthalate, mono-cyclohexyl phthalate, and mono-n-octyl phthalate, suggesting that human exposures to di-isononyl phthalate, dioctylphthalate, and dicyclohexyl phthalate, respectively, are lower than those listed above, or the pathways, routes of exposure, or pharmacokinetic factors such as absorption, distribution, metabolism, and elimination are different. Non-Hispanic blacks had significantly higher concentrations of MEP than did Mexican Americans and non-Hispanic whites. Compared with adolescents and adults, children had significantly higher levels of MBP, MBzP, and MEHP but had significantly lower concentrations of MEP. Females had significantly higher concentrations of MEP and MBzP than did males, but similar MEHP levels. Of particular interest, females of all ages had significantly higher concentrations of the reproductive toxicant MBP than did males of all ages; however, women of reproductive age (i.e., 20-39 years of age) had concentrations similar to adolescent girls and women 40 years of age. These population data on exposure to phthalates will serve an important role in public health by helping to set research priorities and by establishing a nationally representative baseline of exposure with which population levels can be compared.
876 citations
"Decrease in anogenital distance amo..." refers background or methods in this paper
...Despite the growing body of literature on phthalate reproductive toxicity and data demonstrating extensive human exposure (Silva et al. 2004a), few studies have examined the effects of these chemicals on human reproductive development....
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...The analytical approach for the analysis of urinary phthalate metabolites (Silva et al. 2004b) is a modification of previously published methods (Silva et al. 2003)....
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...In the recent National Health and Nutrition Examination Survey (NHANES 1999–2000), most of the general population in the United States had measurable exposure to multiple phthalates (CDC 2003; Silva et al. 2004a)....
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TL;DR: Data indicate that DEHP disrupts male rat sexual differentiation by reducing T to female levels in the fetal male rat during a critical stage of reproductive tract differentiation.
737 citations
"Decrease in anogenital distance amo..." refers background in this paper
...Recent studies have reported significant reductions in anogenital distance (AGD) in SpragueDawley rats after prenatal exposure at high doses to BzBP (Nagao et al. 2000; Tyl et al. 2004), DBP (Barlow and Foster 2003; Foster et al. 2000), and DEHP (Gray et al. 2000; Parks et al. 2000)....
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...In particular, dibutyl phthalate (DBP), benzylbutyl phthalate (BzBP), di-2-ethylhexyl phthalate (DEHP), and di-isononyl phthalate have been shown to disrupt reproductive tract development in male rodents in an antiandrogenic manner (Parks et al. 2000)....
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...DEHP has been shown to shorten AGD (Gray et al. 2000) and reduce testosterone (Parks et al. 2000)....
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