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The Impact of Centrally-acting Pesticidal/Environmental Toxicants on the Neuroendocrine Regulation of Reproductive Function in the Female Rodent: Revelant to Human Reproductive Risk Assessment.
Citation:
GOLDMAN, J M. AND R L. COOPER. The Impact of Centrally-acting Pesticidal/Environmental Toxicants on the Neuroendocrine Regulation of Reproductive Function in the Female Rodent: Revelant to Human Reproductive Risk Assessment. Chapter 9, Eldridge, JC; Stevens JT (ed.), Endocrine Toxicology. Informa Healthcare USA, New York, NY, , 210-239, (2010).
Impact/Purpose:
The role of the brain in triggering the ovulatory surge of luteinizing hormone (LH) in women has been a subject of debate for over 30 years. It is commonly understood that gonadotropin-releasing hormone (GnRH) secreted from the hypothalamic median eminence into portal vessels that descend to the pituitary will stimulate the release of LH. However, it has been questioned whether the mechanisms stimulating GnRH are actively involved in triggering the surge or are merely permissive factors secondary to regulatory control provided by estradiol feedback from the ovaries. In either case, the basic issue for toxicologists is the impact of neurotoxicant exposure on reproductive activity. In the rodent, hypothalamic mechanisms of GnRH are acknowledged to actively participate in generating the LH surge, and it has been argued that differences between humans and rodents signify that neuroendocrine data from the latter have limited relevance in human reproductive risk assessment. This chapter examines the impact on LH of neurotoxicant exposures in women, non-human primates and rodent test species. Comparisons are also made between rodents and humans in the connectivity between GnRH neurons and those neuronal and non-neuronal cells determined to be important to GnRH secretion. Recent comparative data have emphasized the degree of homology that exists between rodents and humans, and that even though some disparities may exist in the nature of hypothalamic participation in triggering the LH surge and ovulation, experimental rodent data provide essential information to The Office of Pesticide Programs and the Office of Science Coordination and Policy for EPA’s efforts in reproductive risk assessment.
Description:
In mammals, the secretion of gonadotropin-releasing hormone (GnRH) from the brain hypothalamic median eminence constitutes the final common path to the pituitary that results in the ovulatory surge of luteinizing hormone (LH). In rodent test species, a growing number of environmental and pharmacological chemicals have been found to interfere with hypothalamic mechanisms that serve to stimulate GnRH release, thereby blocking the LH surge and ovulation. In addition to the impact of increasing concentrations, the effect of such treatments on reproduction in the female rodent is shaped by a variety of exposure parameters, including the duration of treatment and the time of administration during the ovulatory cycle, along with pharmacokinetic factors associated with the absorption, distribution, metabolism and excretion (ADME) of a compound. For the process of human reproductive risk assessment, the relevance of such neuroendocrine data obtained from rodents is dependent (1) on the extent of correspondence between rodents and humans in the functional relationships within the hypothalamus and (2) in the degree of interspecies comparability in ADME for individual endocrine disrupting chemicals. Debate has continued about the contribution of the hypothalamus in reproductive physiology, whether it is permissive or an active participant in generating the LH surge. In either case, the basic issue for toxicologists is the toxicant-induced impact on reproductive activity. As our understanding of the mechanisms regulating hypothalamic secretory activity has progressed, it has become more apparent that the degree of homology between rodents and humans gives weight to the utility of rodent-generated toxicological data in the assessment of reproductive risk in women.