Reproductive and Developmental Toxicology Carole A Kimmel PhD Judy Buelke Sam

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1.0 Introduction

Reproductive toxicology encompasses the study of a wide variety of chemical and physical agents and their effects on the structure and function of the male and female reproductive systems, the ability to conceive and reproduce, the nurture of the young during pregnancy and lactation, and the development of offspring to grow, mature, and reproduce (Fig. 3.1). Developmental toxicology involves the study of the effects of preconceptional, prenatal, and/or postnatal exposures up to the time of sexual maturity on developmental processes. Developmental toxicology is a subset of reproductive toxicology, although the subsequent effects of direct postnatal exposure of young animals or children traditionally have notx been considered part of reproductive toxicology. Reproductive dysfunction and developmental disorders are major public health issues that affect significant proportions of the population. Infertility in humans, defined as the inability to conceive after one year of unprotected intercourse, has been estimated to affect approximately 8% of all married couples in the United States (1). Billions of dollars are spent each year on fertility treatments, including fertility drugs and the increased use of assisted reproductive techniques (e.g., in vitro fertilization). Although many of these technologies can improve fertility, some can also result in multiple births that put small and premature babies at risk. The causes of infertility are varied, and the impact of chemical and physical agents on the reproductive system is unclear. However, several reports in the 1990s of declining human sperm concentration, an increased incidence of cryptorchidism, hypospadias, and testicular cancer, as well as reports that some chemicals may act by disrupting endocrine function (2-5), have raised concerns that environmental chemicals might be causing some of these problems. These concerns have led to requirements, as part of the Food Quality Protection Act of 1996, for testing pesticides and industrial chemicals for their potential to cause endocrine disruption.

Figure 3.1. Reproductive life cycle of the parental and F1 generations showing the major stages in development, reproduction, and aging.

The incidence of spontaneous abortions in the population has been estimated to be as high as 50% of all conceptions (6, 7). Many of these occur before implantation in the uterus, are not detected, and cannot be distinguished from subfertility or infertility. Tests sensitive to the production of human chorionic gonadotropin as early as eight days after conception (before a woman may know she is pregnant) have shown a rate of 32-34% spontaneous abortions for postimplantation pregnancies (8, 9). The incidence of major birth defects in live-born children is 3-4%, and developmental disorders at school age affect approximately 12-14% of all children. The lifetime cost of caring for children born each year with the 17 most common birth defects and cerebral palsy has been estimated to be more than $8 billion. (10). This is a conservative estimate because these birth defects affect only 22% of children born with birth defects in a year and lost wages of caregivers were not considered. Developmental disorders also include the full gamut of functional effects such as neurobehavioral deficits, altered cardiovascular, pulmonary, renal, and other organ system dysfunction that result from prenatal or postnatal exposures.

The contribution of chemical and physical agents to the cases of reproductive dysfunction in humans is unknown, but there are some outstanding examples of environmental chemicals, pharmaceuticals, and other agents that can affect reproduction, development, and function; these include, for example, lead, methylmercury, polychlorinated biphenyls, diethylstilbestrol, thalidomide, cigarette smoking, and alcohol. 1.1 Definitions

Reproductive toxicology is the study of the occurrence of biologically adverse effects on the reproductive systems of females or males that may result from exposure to chemical or physical agents. The toxicity may be expressed as alterations to the female or male reproductive organs, the related endocrine system, or pregnancy outcomes. The manifestations of such toxicity may include,

Growth and Sexual maturation development ^^^

Figure 3.1. Reproductive life cycle of the parental and F1 generations showing the major stages in development, reproduction, and aging.

Growth and Sexual maturation development ^^^

Embryogenesis and fetal development —■— Zygote transport and implantation but are not limited to, adverse effects on the onset of puberty, gamete production and transport, reproductive cycle normality, sexual behavior, fertility, gestation, parturition, lactation, developmental toxicity, premature reproductive senescence, or modifications in other functions that depend on the integrity of the reproductive systems.

Fertility is defined as the capacity to conceive or induce conception.

Fecundity is the ability to produce offspring within a given time period. For litter-bearing species, the ability to produce large litters is also a component of fecundity.

Developmental toxicity is the occurrence of adverse effects on the developing organism that may result from exposure before conception (either parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the life span of the organism. The major manifestations of developmental toxicity include (1) death of the developing organism, (2) structural abnormality, (3) altered growth, and (4) functional deficiency.

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Pregnancy Guide

Pregnancy Guide

A Beginner's Guide to Healthy Pregnancy. If you suspect, or know, that you are pregnant, we ho pe you have already visited your doctor. Presuming that you have confirmed your suspicions and that this is your first child, or that you wish to take better care of yourself d uring pregnancy than you did during your other pregnancies; you have come to the right place.

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