Anti-androgenic Pesticides: Impact on Male ReproductionEPA Grant Number: R826131
Title: Anti-androgenic Pesticides: Impact on Male Reproduction
Investigators: Veeramachaneni, D. N. Rao
Institution: Colorado State University
EPA Project Officer: Klieforth, Barbara I
Project Period: October 1, 1997 through September 30, 2000 (Extended to September 30, 2002)
Project Amount: $454,974
RFA: Endocrine Disruptors (1997) RFA Text | Recipients Lists
Research Category: Economics and Decision Sciences , Health , Safer Chemicals , Endocrine Disruptors
Exposure to pesticides has been implicated as a cause for the increasing incidence of infertility and reproductive disorders such as cryptorchidism and testicular cancer, but substantiating data are scant. The objective of the proposed research is to determine immediate and long-term reproductive sequelae following gestational plus lactational exposures to two anti-androgenic pesticides, individually and in combination. Rabbits were chosen as animal model for studies proposed in this application because the infantile period in this species is relatively long (~12 wk), more closely approximating the situation in humans relative to life span. Furthermore, use of rabbits facilitates serial multiple sampling of blood and semen, enabling longitudinal evaluations. The overall hypothesis to be tested is that exposure to endocrine-disrupting pesticides, even at low concentrations, during differentiation of the reproductive system alters reproductive function as adults.
Rabbit does will be exposed to p,p'-DDT and vinclozolin, individually and as a 50:50 mixture at 0, a low (50 æmol/kg body wt) or a high (500 æmol/kg) dose by gavage on alternate days beginning on gestational day 18 (when organogenesis is complete) until postpartum wk 6 (when pups are weaned). Reproductive sequelae in the male offspring will be determined at crucial stages of sexual development, viz., pre-puberty (at 6 and 12 wk) and post-puberty (24-36 wk). The end points/parameters used to delineate the sequelae will include: 1) characterization of hypothalamo-pituitary-testicular axis by a) determining changes in circulating profiles of luteinizing hormone (LH) and testosterone, b) evaluation of LH content and gonadotropin-releasing hormone (GnRH) receptors in the pituitary gland, GnRH concentration in the hypothalamus, pituitary response to exogenous hypothalamic stimuli (GnRH), and gonadal response to exogenous pituitary stimuli (hCG); 2) assessment of sexual behavior and sexual capacity; 3) quantification of post-pubertal gametogenic efficiency by evaluating a) seminal characteristics, b) daily sperm production rate, and c) the ratios of differentiating germ cell populations; 4) characterization of cellular elements within the seminiferous tubules and interstitium by immunocytochemical means; and 5) evaluation of histopathological changes in reproductive organs.
This proposed work is expected to result in: 1) development of an animal model relevant to human scenario; 2) step-by-step elucidation of endocrine-disrupting effects of pesticides correlating hitherto undocumented structural-functional sequelae, which will be pivotal for establishing causal relationships; and 3) identification of potential biomarkers.