A Practical Approach, Second Edition=Ronald D. Ho.pdf

460 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONmalformation is “a permanent structural change that may adversely affect survival, developmentor function” while a variation is a “divergence beyond the usual range of structural constitutionthat may not adversely affect survival or health.” 11 In rat studies, half of the fetuses are subjectedto visceral evaluation while either the remaining half or all of the fetuses are processed for skeletalevaluations. For a detailed discussion of necropsy, uterine evaluation, and the fetal gross, visceral,and skeletal evaluations used in the developmental toxicity study, see Tyl and Marr. 303. End of Lactation (Segment III Studies)In Segment III and multigenerational studies, the dam is killed after the weaning of the offspringon PND 21. The dam is euthanized, subjected to a complete necropsy, and the reproductive organsand other tissues specified in the protocol are weighed and saved for possible histopathologicalevaluation.E. Female Reproductive Organ Weight1. OvaryOvarian weight in the normal rat does not show significant fluctuations throughout the estrouscycle. However, persistent polycystic ovaries, oocyte depletion, decreased corpus luteum formation,luteal cysts, altered pituitary-hypothalamic function, and reproductive senescence may be associatedwith ovarian weight changes. Ovarian gross morphology and histology should be examined todetect alterations associated with ovarian weight changes.2. Uterus, Oviducts, Vagina, and Pituitary GlandUterine weight fluctuates throughout the estrous cycle, peaking at proestrus, when the uterus isdistended with watery fluid (sometimes misdiagnosed as hydrometra) in response to increasedestrogen secretion. Compounds that inhibit steroidogenesis and cyclicity can cause the uterus tobecome small and atrophic, thereby decreasing the uterine weight. Uterine weight change has beenused as a basis for comparing relative potency of estrogenic compounds in bioassays. 120The oviducts are not routinely evaluated or weighed in reproductive toxicity studies. Theoviductal weight fluctuates depending upon the stage of the estrous cycle. The oviductal lumencontains a variable amount of fluid, which is greatest at metestrus, the period of ovulation. 121 Grossevaluations can be of value in detecting morphologic anomalies, such as agenesis and segmentalaplasia.Vaginal weight changes usually parallel uterine weight changes during the estrous cycle,although the magnitude is less. The vaginal and cervical epithelia show cyclic changes in morphologyand thickness associated with stages of the estrous cycle.Pituitary gland weight can provide information into the reproductive status of the female.Pituitary weight normally increases with age and also increases during pregnancy and lactation.Increased pituitary weight often precedes cancerous lesions induced by estrogenic compounds, andconversely, reduced pituitary weight may result from decreased estrogenic stimulation. 122 However,the pituitary contains other cell types that are responsible for the regulation of a variety ofphysiologic functions unrelated to reproduction. Therefore, changes in pituitary weight do notnecessarily reflect reproductive impairment. Selective histological stains should be used to confirmchanges in regions of the pituitary associated with reproductive functions. If the pituitary weightchanges can be associated with changes in reproductive functions of the pituitary, then such pituitaryweight changes should be considered as adverse female reproductive effects.© 2006 by Taylor & Francis Group, LLC