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

1050 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITION(the interval between menarche and first ovulation) proposed by Young and Yerkes (39). In mostyoung women, ovulation does not occur until 6 or more months after menarche and a regularrecurrence of ovulatory menstrual cycles does not appear to become established until several yearslater (40,41,42,43). The postmenarcheal phase of development in the rhesus monkey is the resultof a high incidence of anovulatory and short luteal-phase cycles (44,45).Estradiol concentrations increase at initial stages of puberty at 2.5 to 3 years in the non-humanprimate (46,47) and at 8 to 10 years in the human (48,49,50,51). Gonadotropes acquire the capacityto respond to the stimulatory action of estradiol on LH secretion after menarche (25,26,27). The onsetof puberty in the human is marked by an increase in the amplitude of LH pulses, which is taken toindicate an increase in the amplitude of GnRH pulses. Studies in the rhesus monkey (28,46,52,53)suggest that the central nervous system mechanisms responsible for the inhibition of the GnRH pulsegenerator during childhood involve primarily gamma-aminobutyric acid (GABA) and GABAergicneurons. With the onset of puberty, the reactivation of the GnRH pulse generator is associated with afall in GABAergic neurotransmission and an associated increase in the input of excitatory amino acidneurotransmitters (including glutamate) and possibly astroglial-derived growth factors (30,54).It appears that adequate levels of leptin and a leptin signal are required to achieve puberty andto maintain cyclicity and reproductive function in the rodent (55,56,57,58,59,60,61), non-humanprimate and human (30,62,63,64). However, leptin does not appear to have a direct effect on thecentral control of the pulsatile release of GnRh (53). The available evidence suggests that leptinacts as one of several permissive factors but alone is not sufficient to initiate sexual maturation.Prolactin has a luteotropic role in rats. The prolactin content and prolactin-containing cells ofthe anterior pituitary increase with postnatal age (65,66) but prolactin levels remain low until theprepubertal period (67,68). Prolactin is not leuteotropic in monkeys or humans (69).In order to aid in pinpointing the timing of landmarks in the postnatal development of thefemale reproductive tract and for cross-species comparisons, Table 2 presents the timing of specificlandmarks for the rat, dog, non-human primate and human, including endocrine status, folliclematuration, ovulation, reproductive tract development, estrous cyclicity/menarche, adrenarche,puberty and fertility.The information in this review may be useful in the interpretation of results from investigationsinto the potential effects of chemical/compound exposures during the development of younganimals. Although this information may also aid in the selection of the most appropriate speciesfor an investigation, it cannot be separated from other issues in the design of a study that impactthe final species selection, including:Study purpose: Is the investigation a primary or screening study, with the primary purpose to identifypotential adverse effects in juvenile animals that are not seen in adults of the same species, or isit secondary/focused study, with the primary purpose of investigating, for example, the scope,severity, potential for recovery, etc., for adverse effects on a specific organ system during postnataldevelopment? What regulatory guidelines must be followed?Exposure window and duration: Based on the purpose of the study, will the exposure be limited toa defined stage in postnatal development or should it include several stages, possibly from neonatalto sexual maturity? Also, do results from previous studies in adults or in young animals, if available,demonstrate changes in no-observed-effect levels over time and/or progression of target organtoxicities with chronic administration? Do considerations of enzyme induction, immature metabolism,and the desired stage(s) of development for exposure limit the species selection?Compound specific considerations: Are there species-specific characteristics for the compound withrespect to the mechanism of action, pharmacokinetics, target organ toxicity, etc., that limit potentialspecies for consideration?Concordance between animal and human toxicity: Are results available (most probably in the adult)that support concordance of target organ toxicity for the compound from animal and human studies?While some of the framing of the preceding questions may be more appropriate for pharmaceuticaldevelopment, they nevertheless provide useful discussion for other types of investigations.© 2006 by Taylor & Francis Group, LLC