Synergistic Disruption of External Male Sex Organ Development by a Mixture of Four Antiandrogens

Abstract

BackgroundBy disrupting the action of androgens during gestation, certain chemicals present in food, consumer products, and the environment can induce irreversible demasculinization and malformations of sex organs among male offspring. However, the consequences of simultaneous exposure to such chemicals are not well described, especially when they exert their actions by differing molecular mechanisms.ObjectivesTo fill this gap, we investigated the effects of mixtures of a widely used plasticizer, di(2-ethylhexyl) phthalate (DEHP); two fungicides present in food, vinclozolin and prochloraz; and a pharmaceutical, finasteride, on landmarks of male sexual development in the rat, including changes in anogenital distance (AGD), retained nipples, sex organ weights, and malformations of genitalia. These chemicals were chosen because they disrupt androgen action with differing mechanisms of action.ResultsStrikingly, the effect of combined exposure to the selected chemicals on malformations of external sex organs was synergistic, and the observed responses were greater than would be predicted from the toxicities of the individual chemicals. In relation to other hallmarks of disrupted male sexual development, including changes in AGD, retained nipples, and sex organ weights, the combined effects were dose additive. When the four chemicals were combined at doses equal to no observed adverse effect levels estimated for nipple retention, significant reductions in AGD were observed in male offspring.ConclusionsBecause unhindered androgen action is essential for human male development in fetal life, these findings are highly relevant to human risk assessment. Evaluations that ignore the possibility of combination effects may lead to considerable underestimations of risks associated with exposures to chemicals that disrupt male sexual differentiation.

Late-life effects on rat reproductive system after developmental exposure to mixtures of endocrine disrupters

“…Shorter anogenital distance in prostate cancer patients was recently shown in a human casecontrol study (Castañ o-Vinyals et al 2012). Developmental exposure to anti-androgens may play a role in prostate cancer development in men, as it is well recognized from animal studies that developmental exposure to anti-androgenic chemicals results in shorter anogenital distance in male rats (Hass et al 2007, Christiansen et al 2009). Anway & Skinner (2008) found an adult onset of mostly augmented atrophic changes and to a lesser extent hyperplastic changes to the aged ventral prostates through four generations following neonatal exposure to vinclozolin in F0 rats.…”

An overall risk probability-based method for quantification of synergistic and antagonistic effects in health risk assessment for mixtures: theoretical concepts

“…There are evidences that estrogenic compounds act either additively (Brian et al, 2005) or mildly synergistically (Christiansen et al, 2009). If we assume the two EDCs do not interact with each other, the ORP for exposure to the mixture of two is P m = 1 -(1 -0.081) (1 -0.27) = 0.33 Equation (17) On the other hand, if we use a synergistic coefficient of 0.10 to represent the interacting effect of the two, the ORP for exposure to the mixture is 1 -P E2 = (1 -0.081) (1 -0.10 x 0.27) = 0.894 Equation (18a) 1 -P EE2 = (1 -0.27) (1 -0.10 x 0.081) = 0.724 Equation ( …”

“…Currently, the only methods that can be used for the quantification of mixture effects are the method of dose addition (Bliss, 1939;Sumpter et al 2006; Thorpe et al 2006) and the method of independent action (or response addition) (Loewe et al, 1926;Silva et al 2002;Christiansen et al 2009). The method of dose addition can be used when the mixture components are assumed to act through a similar or common mode of action (Sumpter et al 2006).…”

In utero and lactational exposure to vinclozolin and genistein induces genomic changes in the rat mammary gland

“…However, few studies have considered the effects of mixtures of EDCs on mammary glands (Foster et al 2004, Wang et al 2006. One way of studying such mixtures involves using combinations of EDCs from the same or different families (Wang et al 2006, Christiansen et al 2009, Eustache et al 2009, Lehraiki et al 2011, taking into account the hormonal environment of normal development.…”

“…Anti-androgens including V have been shown to alter the development of male rat mammary gland. Nipple retention has been identified as a sensitive endpoint for mammary gland development in male rats treated with anti-androgen compounds (Christiansen et al 2009), suggesting that androgens may play an important role in very early sex differentiation of the mammary gland. Gestational dietary exposure to low-dose V and G has also been shown to have antagonistic effects on rat fertility and on fetal germ cell development (Eustache et al 2009, Lehraiki et al 2011.…”