Edited by K. Boekelheide, Brown University, Providence, RI, USA R. Chapin, NIEHS, Research Triangle Park, NC, USA P.B. Hoyer, University of Arizona, Tucson, AZ, USA C. Harris, University of Michigan, Ann Arbor, MI, USA I.G. Sipes C.A. McQueen A.J. Gandolfi, University of Arizona, Tucson, AZ, USA
Description
Section 1, the section on male reproductive toxicology, starts with a basic overview on the anatomy and physiology of the system. This
is followed by reviews on the way molecules are evaluated for male reproductive toxicity in both the pharmaceutical and chemical industries,
along with a strategy for evaluating the reproductive function of transgenic animals. The bulk of this section is devoted to reviewing
mechanisms and manifestations of toxicants to particular targets within the male reproductive system (Sertoli cell, Leydig cell, etc.).
Finally, a significant part evaluates areas of interest not often considered in the toxicologic context (fluid flow, the immune system,
paracrine factors, etc.), as well as a part highlighting technical advances and what these mean for the field. Overall, this volume reviews
the state of the science in a number of areas, explicitly provides strategies for investigators to use in addressing their own problems,
and then looks forward to identify promising areas of future research. It is a most significant contribution to the field.
Section
2 provides a comprehensive overview of the field of female reproductive toxicology. Much interest has recently become focused on this
area of toxicology, due to the increase in numbers of women in the workplace, and the impact of female fertility on reproduction issues.
This section begins with an overview of female reproductive physiology, with an emphasis on the complexities of its hormonal regulation.
Next, the various components of the female reproductive system are described in detail, along with known and potential sites of disruption
by xenobiotics. Finally, assessment of human risk is discussed from the standpoint of classical methods of evaluation, as well as recently
developed, novel experimental approaches.
Section 3 provides an overview of mammalian development, from fertilization to parturition
and early postnatal maturation, in terms of the stage-selective anatomical and functional characteristics of each developmental phase
that may underpin the ultimate manifestations of toxicity which have been observed. Several possible mechanisms of developmental toxicity
are discussed in terms of the roles of biotransformation, pharmacokinetics, altered gene expression, neurobehavioral development, physiological
conditions, and nutritional status. A selected list of chemical agents and environmental extremes known to produce persistent developmental
abnormalities is reviewed by class and are discussed in terms of their known toxic effects and possible mechanisms of action. Strategies
for the study of developmental toxicants in vivo and in vitro are described, as well as current screening and testing
systems for the detection of additional potential disrupters of normal development. This section concludes with a summary and discussion
of the critical needs for additional understanding and the future prospects for accurate prediction, prevention and assessment of risk
in developmental toxicity.
Volume 10 concludes with five chapters that discuss the effects of chemicals on various endocrine tissues.
These include the thyroid and parathyroid glands, the adrenal cortex and medulla, and the insulin secreting beta-cells of the pancreas.
Since these tissues secrete hormones that cause profound biochemical and physiological effects on the body, the activities of these
glands are tightly controlled, primarily by circulating factors. For example, trophic factors released by the pituitary gland upregulate
the activities of the thyroid gland and the adrenal cortex. The pituitary gland is further regulated by releasing factors produced in
the hypothalamus. Thus, the hypothalamus-pituitary-endocrine gland axis, provides for the fine regulatory control of hormone secretion.
It is apparent, then, that chemicals can affect endocrine function either directly, at the level of endocrine gland, or indirectly at
the level of the hypothalamus-pituitary. However, the situation is even more complex. Since chemicals that alter the metabolism of the
hormone (i.e. enzyme induction or inhibition in the liver) can cause an imbalance in the "axis", with dramatic effects on the endocrine
gland and ultimately on other tissues of the body. The various chapters provide examples of drugs, model toxicants, and environmental
pollutants that disrupt endocrine function. These disruptions result in such toxicities such as diabetes, hypertension, thyroid tumors,
immune dysfunction, bone disorders, among others.
Contents
Section 1: Male Reproductive Toxicology (K. Boekelheide, R.E. Chapin). Male Reproductive Toxicology (K. Boekelheide, R.E. Chapin).
Anatomy and physiology of the male reproductive system and potential targets of toxicants (L. Johnson, T.H. Welsh, Jr, C.E. Wilker).
Evaluation of a toxicant (P.M.D. Foster). Evaluation of an investigational new drug (W.F. Blazak). Evaluation of an infertile transgenic
animal (E.M. Eddy). Hypothalamic-pituitary-gonadal- axis/lead (R.Z. Sokol). Testis xenobiotic metabolizing enzymes (M.G. Miller).The
Leydig cell: mechanisms of toxicity (W.R. Kelce). Sertoli cell (J.H. Richburg, K.T. Blanchard, K. Boekelheide). Germ cell toxicants (R.E.
Chapin). Ethane dimethylsulfonate: a prototypic epididymal toxicant (G.R. Klinefelter). The mature spermatozoa as a target for reproductive
toxicants (S.D. Perreault). Environmental endocrine disruptors (R.E. Peterson, P.S. Cooke, W.R. Keice, L.E. Gray Jr). Leydig cell tumors
(J.C. Cook, S.R. Frame, J.D. Odbourn). Immunology of the testis and sperm (M.P. Hedger). Technical advances (K.T. Blanchard, J. Lee).
Fluid flow and vasomotion (R.M. Sharpe). Unconventional models for toxicology research (G.V. Callard, M. Betka, D. Miller).
Section
2: Female Reproductive Toxicology (P.B. Hoyer). Female reproductive toxicology: introduction and overview (P.B. Hoyer). Differentiation
and function of the female reproductive system (A.R. LaBarbera). Neuroendocrine control of female reproduction regulation (R.L. Cooper).
Reproductive, developmental, and endocrine toxicology (A.N. Hirshfield, J.A. Flaws). Ovarian cancer: experimental and genetic models
in the mouse (W. Beamer). Ovulation, oocyte maturation, and oocyte function (S.D. Perreault, J.M. Goldman). Embryo-uterine interactions
during implementation: potential sites of interference by environmental toxins (S.K. Das, B.C. Paria, D.C. Johnson, S.K. Dey). Chemically
induced alterations of reproductive development in female mammals (L.E. Gray, Jr). Lactation and contamination of breast milk with xenobiotics
(P. Bennett). Risk assessment studies: fertility/multigenerational studies (J.M. Rogers). Species specificity: integration from a clinical
perspective (J.F. Jarrell, J.E. Seidell). Risk assessment studies: epidemiology (E.A. Whelan). Ovarian perfusion (J.F. Jarrell, M.L.
Sevcik). New directions in experimental approaches - follicular isolations (J.A. Flaws, P.B. Hoyer). Mechanisms and genes of physiological
risk assessment? (J.L. Tilly). Transgenic mouse models with altered expression of the estrogen receptor (V.L. Davis, J.F. Couse, K.S.
Korach).
Section 3: Developmental Toxicology (C. Harris). Introduction to developmental toxicology (C. Harris). Preimplantation
embryogenesis (E.W. Carney). Postimplantation embryotoxicity: anatomy, physiology, and function (C. Harris). Fetotoxicity (C. Harris).
Parturition (R. Loch-Caruso, T.R. Krieger). The role of biotransformation in developmental toxicity (P.G. Wells, L.M. Winn). Pharmacokinetic
and structure-activity considerations (D.O. Clarke). Genetic and cellular pathways in teratogen-induced cell death (T.B. Knudsen). Alterations
of biochemical pathways, metabolism and physiological processes (C. Harris). Neurobehavioral effects of in utero exposures (J.W.
Henck). Selected examples of developmental toxicants (R.E. Seegmiller). Hyperthermia, heat shock proteins, and developmental toxicity
(P.E. Mirkes). In vivo and in vitro methods in developmental toxicology (C. Harris). In vivo animal screening
and testing systems (J.W. Henck).
Section 4: Endocrine Toxicology (I.G. Sipes, A.J. Gandolfi). Toxic responses of the adrenal
cortex (J.T. Yarrington, J.R. Latendresse, C.C. Capen). Toxic responses of the adrenal medulla (A.S. Tischler). Toxic responses of the
parathyroid gland (C.C. Capen). Toxic responses of the thyroid gland (C.C. Capen). Toxicity to the insulin-secreting beta cell (L.J.
Fischer).
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