Sexual differentiation

TABLE 33.1. Examples of Known and Potential Endocrine Disrupting Chemicals (EDCs) and Their Postulated Mechanisms 

Estrogen receptor Diethylstilbestrol Methoxychlor Bisphenolic compounds Genistein Zearalenone Progesterone receptor Dimethistrone Norethindrone 

Anastrazole (Arimidex ) (CYP19A1 inhibitor) Letrozole (Femara ) (CYP19A1 inhibitor) Finasteride (SRD5A inhibitor) 

Ethane dimethantesulfonate (Leydig cell toxicant) Pthalates (Granulosa cell and Sertoli cell toxicants) 

Sexual differentiation of the central nervous system also occurs during fetal development, and it is equally fundamental to reproductive function during adulthood. Adult males exhibit a relatively continuous pattern of gonadotropin secretion from the hypothalamic-pituitary axis and are therefore fertile throughout their reproductive lifetime. In contrast, adult females exhibit a cyclical pattern of gonadotropin secretion and are fertile only during the transient period that follows ovulation during each reproductive cycle. This fundamental difference is due to irreversible 

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Female sexual development and behaviour in mammals occurs by default and requires no ovarian secretion, and it is only in genetic males that the testis can secrete hormones which destroy this female pattern and superimpose that of the male. Sexual differentiation is not so well defined in fish, and larval exposure to both synthetic estrogens and androgens is widely used in aquaculture to produce monosex cultures. Endocrine disruption of sexual differentiation in fish may therefore reflect both the complexity and diversity of such processes between different species. Some care is required in use of the terms hermaphrodite and sex-reversal since a true hermaphrodite has both functional testes and ovaries and a sex-reversed fish is fully functional as its final sex—both produce the appropriate viable gametes. Such functional sex-reversal is not possible in mammals, but in some species of fish it is the normal developmental pattern. In most of the cases of hermaphroditism or sex-reversal reported in the non-scientific press, there is evidence only for a few ovarian follicles within a functional testis. This may be considered as feminisation or a form of intersex, and is very clearly endocrine disruption, but it is certainly neither sex-reversal nor hermaphroditism. In some cases the terms have even been used to infer induction of a single female characteristic such as production of yolk-protein by males. 

Analysis of ESRB 7 mice showed fewer and smaller litters than wild type mice as well as abnormal vascular function and hypertension. The reduction in fertility was attributed to reduced ovarian efficiency. Mutant females had normal breast development and lactated normally. Older mutant males displayed signs of prostate and bladder hyperplasia. s -2-deficient mice furthermore display diverse regulatory defects in the function of brain, lung, and white blood cells. The results indicated that ESRB is essential for normal ovulation efficiency but is not essential for lactation, female or male sexual differentiation, or fertility. 

Gray LE, Ostby J, Wolf C, et al. 1998. The value of mechanistic studies in laboratory animals for the prediction of reproductive effects in wildlife Endocrine effects of mammalian sexual differentiation. Environ Toxicol Chem 17(1) 109-118. 

Gray, L.E., Ostby, J., and Wolf, C. et al. (1996). Effects of estrogenic, antiandrogenic and dioxin-like synthetic chemicals on mammalian sexual differentiation. Abstracts of Papers of the American Chemical Society 212,4—TOXI. 

Fig. 5.11 Output rate from VN epithelia in male mice sexually differentiated responses to male (1.) and to female (2.) urine, [time = sec] -50% neurones preferentially respond to like- or to opposite-sex urine ( 300 x dilution) (from Holy et al, 2000).

Sexually differentiated responses to female-soiled bedding occur within the regions of the AOB only the rostral zone was -activated in males as opposed to that of females the caudal zone cells had no such differential activation VN-x removed the response (Dudley and Moss, 1999 Matsuoka et al., 1999). The number of Fos-ii cells was larger after exposure to females of ICR stain, than to BALB females. Male strain-differences gave equivalent amounts of rostral/caudal activity in females. It is probable that discrimination by females of between-strain chemosignals is related to the fine distinctions possible through the operation of cues related to influence of products from the MHC loci. 

Cooke B., Hegstrom C.D., Villeneuve L.S. and Breedlove S.M. (1998). Sexual differentiation of the vertebrate brain principles and mechanisms. Front Neuro-endocrinol 19, 323-362. 

Ulibarri C. and Yahr R (1996). Effects of androgens and estrogens on sexual differentiation of sex behavior, scent marking and the sexually dimorphic area of the gerbil hypothalamus. Horn Behav 30, 107-130. 

Gray L.E. Chemical-Induced Alterations of Sexual Differentiation A Review of Effects in Humans and Rodents / / Chemically-Induced Alterations in Sexual and Functional Development The Wildlife/Human Connection / Ed. T.Colbom, C.Clement. Princeton Sci. Publ., 1992. P.203-230. 

Sokol RZ Health Research Association, Inc., Los Angeles, CA Pb exposure in utero may induce an inherited change in DNA methylation patterns in Pb exposed pups, the mechanism by which Pb exposure during the critical time of sexual differentiation induces reproductive axis abnormalities in adulthood National Institute of Environmental Health Sciences... 

Andersen L, Holbech H, Gessbo A, Norrgren L, Petersen GI (2003) Effects of exposure to 17 alpha-ethinylestradiol during early development on sexual differentiation and induction of vitellogenin in zebrafish (Danio rerio). Comp Biochem Physiol C-Toxicol Pharmacol 134 365-374... 

Goy, R. and McEwen, B. S. Sexual Differentiation of the Brain. Cambridge MIT Press, 1980, notes p223. 

McEwen, B. S. Gonadal steroid influences on brain development and sexual differentiation. In Reproductive Physiology IV. Ed Greep, R. University Park University Park Press, 1983, pp99-145. 

CooperJR, Vodicnik MJ, Gordon JH. 1985. Effects of perinatal Kepone exposure on sexual differentiation of the rat brain. Neurotoxicology 6(1) 183-190. 

Gray LE, Ostby J, Eurr J, Price M, Veeramachaneni DNR, Parks L (2000) Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicol Sci 58 350-365... 

The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat. Toxicol Sci 58 339-349... 

Tavera-Mendoza L, Ruby S, Brousseau P, Fournier M, Cyr D, Marcogliese, D (2002a) Response of the amphibian tadpole (Xenopus laevis) to atrazine during sexual differentiation of the testis. Environ Toxicol Chem 21 527-531... 

These processes include cell proliferation, embryonic development, and sexual differentiation—i. e., processes that require a prolonged time period and involve proteins de novo synthesis. For this reason, mainly steroid hormones which function via transcription regulation are active in this field (see p. 244). 

Of the numerous hormones that regulate body function, two steroid hormones are extremely important estradiol, a female sex hormone and testosterone, a male sex hormone. Present in the body in insignificant amounts, they regulate sexual differentiation and reproduction as well as affect the performance of many other physiological systems. Despite the great similarity in chemical structure, they are very different in terms of physiological action. 

Bogi C., G. Levy, I. Lutz, and W. Kloas (2002). Functional genomics and sexual differentiation in amphibians. Comparative Biochemistry and Physics B 133 559-570. 

Two important aspects of early development of the reproductive tract are that the fetal gonad is structurally indifferent in male and female embyros and that the fetal reproductive system can therefore develop as male or female. Thus, the first major step in development of the reproductive system is establishing gonadal sex. Sex of the embryo depends on whether the spermatozoon carries an X or Y chromosome, and sexual differentiation of the indifferent structures in the gonad is necessary to form the male or female reproductive tract. The SRY gene on the Y chromosome is needed for testicular... 

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