Cumulative Effects of In Utero Administration of Mixtures of "Antiandrogens" on Male Rat Reproductive Development

MD-72, Endocrinology Branch, Reproductive Toxicology Division, NHEERL, ORD, U.S. Environmental Protection Agency, RTP, North Carolina 27713, USA.
Toxicologic Pathology (Impact Factor: 2.14). 02/2009; 37(1):100-13. DOI: 10.1177/0192623308329478
Source: PubMed


Although risk assessments are typically conducted on a chemical-by-chemical basis, the 1996 Food Quality Protection Act (FQPA) required the Environmental Protection Agency (EPA) to consider cumulative risk of chemicals that act via a common mechanism of toxicity. To this end, we are conducting studies with mixtures to provide a framework for assessing the cumulative effects of "antiandrogenic" chemicals. Rats were dosed during pregnancy with antiandrogens singly or in pairs at dosage levels equivalent to about one half of the ED50 for hypospadias or epididymal agenesis. The pairs include: AR antagonists (vinclozolin plus procymidone), phthalate esters (DBP plus BBP and DEHP plus DBP), a phthalate ester plus an AR antagonist (DBP plus procymidone), and linuron plus BBP. We predicted that each chemical by itself would induce few malformations; however, by mixing any two chemicals together, about 50% of the males would be malformed. All binary combinations produced cumulative, dose-additive effects on the androgen-dependent tissues. We also conducted a mixture study combining seven "antiandrogens" together. These chemicals elicit antiandrogenic effects at two different sites in the androgen signaling pathway (i.e., AR antagonist or inhibition of androgen synthesis). In this study, the complex mixture behaved in a dose-additive manner. Our results indicate that compounds that act by disparate mechanisms of toxicity display cumulative, dose-additive effects when present in combination.

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    • "A previous report has suggested that butyl benzyl phthalate (BBP) and linuron, both possessing anti-androgenic properties, produce dose additive effects on reproductive tract development (Hotchkiss et al., 2004). Similarly, another study involving seven anti-androgenic chemicals including a combination of three phthalates, BBP, dibutyl phthalate (DBP), and di (2-ethylhexyl) phthalate (DEHP) showed cumulative effects on androgen dependent reproductive functions (Rider et al., 2009). However, these dose addition models were already criticized by EPA due to non-congruent dose responses (EPA, 2000). "
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    ABSTRACT: Phthalates are commonly used as plasticizers in a variety of products. Since it has been identified as endocrine-disrupting chemical (EDC), effect of phthalates on human health is a major concern. In this study, we evaluated individual as well as combined mixture effects of three low molecular weight phthalates on the reproductive system of male mice, specifically on the Sertoli cell structure and function. In order to analyze the blood testes barrier (BTB) dynamics, primary culture of Sertoli cells from three-week old male mice was used for mimicking typical tight junction structures. Male mice were exposed to long-term (45 days) and combined mixture of three phthalates, diethyl phthalate (DEP), diphenyl phthalate (DPP), and dimethyl isophthalate (DMIP) between pre-pubertal to adult stage. Our data showed significant decrease (p < 0.05) in the rates of transcription of certain prominent Sertoli cell specific genes like transferrin, testin and occludin. Moreover, we also observed significant decreases in the expression of proteins like 3β-HSD, connexin-43 and occludin in testicular lysates of treated animals (p < 0.05). The transmission electron microscopic analysis revealed that the test compounds significantly altered the structural integrity of Sertoli cells. The significant changes of Sertoli cell tight junction structure by test compounds were associated with phosphorylation of ERK. Taken together, our study suggests that low molecular weight phthalates may affect male fertility by altering both structural and functional integrity of Sertoli cells in testes.
    General and Comparative Endocrinology 09/2014; 215. DOI:10.1016/j.ygcen.2014.09.012 · 2.47 Impact Factor
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    • "De nombreuses e ´tudes ont tenté de trouver des facteurs de risque. Les plus fréquemment mis en cause et statistiquement significatifs sont d'ordre : vasculaire (petit poids a ` la naissance, prématurité, prée ´clampsie et insuffisance placentaire, gémellité) ; endocrinien, en particulier les perturbateurs endocriniens [1] via la dérégulation du métabolisme lipidique, glucidique et hormonal [2], notamment les médicaments pris avant (fécondation in vitro [FIV]) et pendant la grossesse comme le clomifène, l'hormone folliculo-stimulante (FSH), la progestérone , le diéthylstilbestrol (DES) [3] et les anti-inflammatoires non stéroı¨diens (AINS) [4] ; environnemental [5] (tabagisme, alcoolisme, présence de pesticides dans les eaux, vie non urbaine) ; génétique [6], comme le montrent les antécédents familiaux. Quelles que soient leur fréquence et leur gravité, ces anomalies doivent retenir l'attention du praticien en raison de leur e ´ventuel retentissement psychologique. "
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    ABSTRACT: Abnormalities of the male genitalia have increased in the last 2 decades in numerous developed countries and remain a frequent reason of consultation in pediatric surgery. The diagnostic spectrum is wide, and surgeons should pay particular attention to these abnormalities because of their potential psychological effect. Anatomically, these abnormalities can affect one of three parts of the penis. First, the foreskin may not be fully retracted. This is normal at birth and can be caused by prepuce adherents that can continue until adolescence. Today, true phimosis is treated with topical corticoids from the age of 3 years. If medical treatment fails, a surgical procedure is required. Second, the urethra can be affected by hypospadia, which is the most frequent abnormality of the urethra. It is associated with ectopic urethral meatus, hypoplastic foreskin, and penis curvature. Its pathogenic background is not clearly understood. Surgery options differ according to the type of hypospadia and according to the surgeon's experience. It is sometimes hard to deal with, especially in a perineal form, where genetic and hormonal studies are recommended. These interventions can lead to complications ranging from stenosis to fistula. Therefore, parents have to be informed of the benefits and risks of the surgical procedures. Epispadias is rare but more serious because of the increasing risk of urinary incontinence. Finally, abnormalities of the corpora cavernosa — often associated with hypospadias — can include penis curvature and micropenis, for which an endocrinological analysis is essential.
    Archives de Pédiatrie 12/2012; 19(12):1347–1353. DOI:10.1016/j.arcped.2012.09.014 · 0.41 Impact Factor
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    • "ter no observable effect assump - tion , Metzdorff et al . ( 2007 ) reported that 5 mg / kg / day procymi - done produced statistically significant changes in seminal vesicle weight , and 10 mg / kg / day produced changes in testis , ventral pros - tate , levator ani / bulbocavernosus muscle , and bulbourethral gland weights , thus suggesting that Rider et al . ( 2009 ) were testing mix - tures containing doses of procymidone well within the observable effect range for anti - androgenic action . Further , although Rider et al . ( 2008 ) reported that vinclozolin was without statistically sig - nificant effects at 3 . 75 mg / kg / day , Metzdorff et al . ( 2007 ) reported that a slightly higher dose o"
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    ABSTRACT: The 2008 National Research Council report "Phthalates and Cumulative Risk Assessment: Tasks Ahead," rejected the underlying premises of TEQ-like approaches - e.g., chemicals are true congeners; are metabolized and detoxified similarly; produce the same biological effects by the same mode of action; exhibit parallel dose response curves - instead asserting that cumulative risk assessment should apply dose addition (DA) to all chemicals that produce "common adverse outcomes" (CAOS). Published mixtures data and a human health risk assessment for phthalates and anti-androgens were evaluated to determine how firmly the DA-CAOS concept is supported and with what level of statistical certainty the results may be extrapolated to lower doses in humans. Underlying assumptions of the DA-CAOS concept were tested for accuracy and consistency against data for two human pharmaceuticals and its logical predictions were compared to human clinical and epidemiological experience. Those analyses revealed that DA-CAOS is scientifically untenable. Therefore, an alternative approach was developed - the Human-Relevant Potency-Threshold (HRPT) - that appears to fit the data better and avoids the contradictions inherent in the DA-CAOS concept. The proposed approach recommends application of independent action for phthalates and other chemicals with potential anti-androgenic properties at current human exposure levels.
    Regulatory Toxicology and Pharmacology 10/2011; 62(2):313-28. DOI:10.1016/j.yrtph.2011.10.012 · 2.03 Impact Factor
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