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Modulation of Adrenal Steroidogenesis by Environmental Chemicals and the Impact on reproductive function.
LAWS, S C., T E. STOKER, M P. FRAITES, R L. COOPER, AND N. TINFO. Modulation of Adrenal Steroidogenesis by Environmental Chemicals and the Impact on reproductive function. U.S. Environmental Protection Agency, Washington, DC.
This research effort is to identify the mechanisms through which environmental chemicals alter adrenal steroidogenesis and to determine the impact of adrenal dysregulation on the neuroendocrine control of ovulation and reproductive function.
This project was based upon outcomes from earlier work conducted under APM 465 to test the hypothesis that the chlorotriazine herbicide, atrazine (ATR), causes an increase in serum estrogens through an induction of aromatase (CYP19) gene expression. The current research has involved a thorough investigation of the possibility that ATR affects estrogen production in vivo through an up-regulation of aromatase activity, as has been widely hypothesized throughout the scientific community based upon in vitro studies. Although this mode of action (MOA) is supported with our in vitro data, no direct effects on aromatase activity or gene expression have been observed following in vivo exposure in the rat. However, our in vivo studies clearly demonstrate that atrazine induces adrenal steroidogenesis , and that this is mediated through an activation of pituitary ACTH secretion. This observation raised important new questions about how environmental agents can affect endocrine function. In particular, with regard to the chlorotriazines, we are investigating whether or not the effect on the adrenals was mediated through a neuroendocrine MOA, as previously determined for the effects on the pituitary-hypothalamus-gonadal (HPG) axis (Cooper et al., 2007), or rather is a direct effect on the pituitary-adrenal axis itself. Because there is a complex interaction between ovarian and adrenal hormones in the regulation of the preovulatory surge of luteinizing hormone (LH), it is critical to understand the role that adrenal dysregulation may play in the reproductive effects that have been identified following exposure to ATR and other environmental chemicals. Data from these studies were used in three briefings (2006 – 2008) for the Office of Water (OW) and Office of Pesticides Program (OPP) to update them on the MOA and adverse effects of the chlorotriazines/primary metabolites. In addition, this research effort brings a new area of expertise to the Agency. Alteration of adrenal function can cause a myriad of adverse health effects such as changes in metabolism, immune responses, steroidogenesis, and reproductive function and development, as well as endocrine mediated diseases. However, while the adrenal is one of the most common toxicological targets of all the endocrine organs, the role that adrenal dysregulation may play in producing any adverse effects observed in toxicology studies is not well defined. The Tier I Screening (TIS) Battery for the Agency’s Endocrine Disruptor Screening Program (EDSP) currently includes only a single endpoint (adrenal weight) in the male pubertal assay as a screen for adrenal toxicity. Thus, research conducted under this project, as well as our ongoing studies under the EDC MYP (LTG 1, APM 195, and LTG 3 (Support to the Agency’s Screening and Testing Program), will identify new approaches for evaluating and understanding the cellular mechanisms responsible for the altered adrenal steroidogenesis.