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ADVERSE EFFECTS OF ANTIANDROGENIC PESTICIDES AND TOXIC SUBSTANCES ON REPRODUCTIVE DEVELOPMERNT IN THE MALE.
Gray, L. Earl1, Hotchkiss, Andrew2, Price, Matt2, Wolf, Cynthia1,3, Furr, Johnathan1, Ostby, Joseph1, Lambright, Christy1, Parks, Louise1, Wilson, Vickie1, Bobseine, Kathy1, Hartig, Phillip1, 1 2 3
ABSTRACT- Anthropogenic endocrine disrupting chemicals (EDCs) or chemical mixtures alter androgen-response tissues via a variety of mechanisms including mimicking or blocking the action of the natural ligand to the androgen receptor (AR), inhibiting steroid hormone synthesis or by acting and aryl hydrocarbon receptor (AhR) agonist. Pesticides like vinclozolin (V), procymidone (P), fenitrothion (F), p,p' DDE (and other DDT metabolites) and linuron (L) are AR ligands that inhibit androgen-induced gene expression in vitro. Some of these also have been shown to alter AR-dependent gene expression in vivo (V, DDE, L). V, P, p.p' DDE and L induce reproductive malformations in male rats. The fetal concentrations of p,p'DDE in affected male rats is 1-20 ppm, similar to that reported for human fetal tissues sampled in the late 1960s. V also has been shown to alter the development of sexual dimorphic behaviors in both the rat and rabbit. Some phthalate esters (PE) like DEHP. DBP, BBP and DINP alter sexual differentiation of the male rat by inhibiting testicular testosterone synthesis. In contrast to AR antagonists, PEs induce a relatively high incidence of epididymal and testicular lesions along with malformations of the external genitalia. AhR agonists like TCDD and PCB 169 affect sexual differentiation of the reproductive tract in male and female rats at low dose levels (fetal TCDD concentrations of 5-40 ppt ). The profile of effects produced by these AhR agonists differs from those produced by AR antagonists or the PEs (no effect on anogenital distance, nipple retention, or hypospadias) with treated males displaying delayed puberty, reduced sex accessory organ weights and lower epididymal and ejaculated sperm counts. For AR antagonists and PEs, anogenital distance reductions (at birth) and nipple/areola retention in infant rats are 1) sensitive "biomarkers" of gestational treatment, and 2) they are persistent effects that are 3) highly correlated with malformations and permanent reproductive organ weight changes in the offspring. Recently, EDCs with androgenic activity were identified. In contrast to the antiandrogens, androgen exposure during sexual differentiation profoundly affects the female rat fetus without obviously affecting male development. While some of the above EDCs produce dose-response curves with a threshold, others appear low-dose linear (with no apparent threshold) or are U-shaped. Studies with mixtures of EDCs demonstrate that toxicants that induce malformations in androgen-dependent tissues produce cumulative effects even when two chemicals act via different mechanisms of action (i.e. AR antagonist vs a PE). In summary, the reproductive system of the male fetus can be adversely affected by EDCs displaying a variety of mechanisms of action. This abstract does not reflect USEPA policy.
KEY WORDS: antiandrogens, male reproductive tract malformations, phthalate esters, TCDD and PCBs
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