Reproductive stages

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The different stages of reproduction are, in fact, highlights of a continuum. These stages concern a different developmental time-span, each with its own sensitivity to a given toxic agent.

Table 1.1. Reproductive stages: organs and functions potentially affected by toxicants

Reproductive stage Female

Germ cell formation Oogenesis (occurs during fetal development of mother) Gene replication Cell division Egg maturation Hormonal influence on ovary Ovulation

Fertilization Oviduct contractility secretions Hormonal influence on secretory and muscle cells Uterus contractility secretions Nervous system behavior libido

Implantation Changes in uterine lining and secretions Hormonal influence on secretory cells


Spermatogenesis Gene replication Cell division

Sperm maturation Sertoli cell influence Hormonal influence on testes

Accessory glands Sperm motility and nutrition

Hormonal influence on glands

Nervous system erection ejaculation behavior libido

Possible endpoints

Sterility, subfecundity, damaged sperm or eggs, chromosomal aberrations, menstrual effects, age at menopause, hormone imbalances, changes in sex ratio

Impotence, sterility, subfecundity, chromosomal aberrations, changes in sex ratio, reduced sperm function

Impotence, sterility, subfecundity, chromosomal aberrations, changes In sex ratio, reduced sperm function

Spontaneous abortion, embryonic resorption, subfecundity, stillbirths, low birth weight





Uterus yolksac placenta formation Embryo cell division, tissue differentiation, hormone production, growth

Placenta nutrient transfer hormone production protection from toxic agents Embryo organ development and differentiation growth Maternal nutrition

Fetus growth and development Uterus contractility Hormonal effects on uterine muscle cells Maternal nutrition

Infant survival Lactation

1 General commentary on drug therapy and drug risks in pregnancy

Spontaneous abortion, other fetal losses, birth defects, chromosomal abnormalities, change in sex ratio, stillbirths, low birth weight

Birth defects, spontaneous abortion, fetal defects, death, retarded growth and development, functional disorders (e.g. autism), transplacental carcinogenesis

Premature births, births defects (particularly nervous system), stillbirths,neonatal death, toxic syndromes or withdrawal symptoms in neonates

Mental retardation, infant mortality, retarded development, metabolic and functional disorders, developmental disabilities (e.g. cerebral palsy and epilepsy)


Primordial germ cells arc present in the embiyo at about 1 month after the first day of the last menstruation. They originate from the yolksac-entoderm outside the embtyo. and migrate into the undifferentiated primordia of gonads located at the medio-ventral surface of the urogenital ridges. They subsequently differentiate into oogonia and oocytes, or into spermatogonia. The oocytes in postnatal life are at an arrested stage of the meiotic division. This division is restarted much later after birth, shortly before ovulation, and is finalized after fertilization with the expulsion of the polar bodies. Thus, all-female germ cells develop prcnatally and no germ cells are formed afterbirth. Moreover, during a female lifespan approximately 400 oocytes undergo ovulation. All these facts make it possible to state that an 8-weeks' pregnant mother of an unborn female is already prepared to be a grandmother!

The embryonal spermatogenic epithelium, on the contrary, divides slowly by repeated mitoses, and these cells do not differentiate into spermatocytes and do not undergo meiosis in the prenatal period. The onset of meiosis in the male begins at puberty. Spermatogenesis continues throughout (the reproductive) life.

When the complexity of sexual development and female and male gametogenesis is considered, it becomes apparent that pre-and postnatal drug exposure is a special toxicological problem having different outcomes. The specificity of the male and female developmental processes also accounts for unique reactions to toxic agents, such as drugs, in both sexes.

After fertilization of the oocyte by one of the spermatozoa in the oviduct, there is the stage of cell divisions and transport of the blastocyst into the endocrine-prepared uterine cavity. After implantation, the bilaminar stage is formed and embryogenesis starts. The next 7 weeks are a period of finely balanced cellular events, including proliferation, migration, association and differentiation, and programmed cell death, precisely arranged to produce tissues and organs from the genetic information present in each conceptus. During this period of organogenesis, rapid cell multiplication is the rule. Complex processes of cell migration, pattern formation and the penetration of one cell group by another characterize the later stages.

Final morphological and functional development occurs at different times during fetogenesis, and is mostly only completed after birth. Postnatal adaptation characterizes the passage from intra- into extrauterine life with tremendous changes in, for example, circulatory and respiratory physiology (see also Table 1.1; Miller 2005).

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