Vol. 1 - Pages 9.1-9.30 (Printed Version)

Reproductive System

REPRODUCTIVE SYSTEM: INTRODUCTION

Lowell E. Sever

Male and female reproductive toxicity are topics of increasing interest in consideration of occupational health hazards. Reproductive toxicity has been defined as the occurrence of adverse effects on the reproductive system that may result from exposure to environmental agents. The toxicity may be expressed as alterations to the reproductive organs and/or the related endocrine system. The manifestations of such toxicity may include:

·       alterations in sexual behaviour

·       reduced fertility

·       adverse pregnancy outcomes

·       modifications of other functions that are dependent on the integrity of the reproductive system.

Mechanisms underlying reproductive toxicity are complex. More xenobiotic substances have been tested and demonstrated to be toxic to the male reproductive process than to the female. However, it is not known whether this is due to underlying differences in toxicity or to the greater ease of studying sperm than oocytes.

Developmental Toxicity

Developmental toxicity has been defined as the occurrence of adverse effects on the developing organism that may result from exposure prior to 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:

·       death of the developing organism

·       structural abnormality

·       altered growth

·       functional deficiency.

In the following discussion, developmental toxicity will be used as an all-inclusive term to refer to exposures to the mother, father or conceptus that lead to abnormal development. The term teratogenesis will be used to refer more specifically to exposures to the conceptus which produce a structural malformation. Our discussion will not include the effects of postnatal exposures on development.

Mutagenesis

In addition to reproductive toxicity, exposure to either parent prior to conception has the potential of resulting in developmental defects through mutagenesis, changes in the genetic material that is passed from parent to offspring. Such changes can occur either at the level of individual genes or at the chromosomal level. Changes in individual genes can result in the transmission of altered genetic messages while changes at the chromosomal level can result in the transmission of abnormalities in chromosomal number or structure.

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It is interesting that some of the strongest evidence for a role for preconception exposures in developmental abnormalities comes from studies of paternal exposures. For example, Prader-Willi syndrome, a birth defect characterized by hypotonicity in the newborn period and, later, marked obesity and behaviour problems, has been associated with paternal occupational exposures to hydrocarbons. Other studies have shown associations between paternal preconception exposures to physical agents and congenital malformations and childhood cancers. For example, paternal occupational exposure to ionizing radiation has been associated with an increased risk of neural tube defects and increased risk of childhood leukaemia, and several studies have suggested associations between paternal preconception occupational exposure to electromagnetic fields and childhood brain tumours (Gold and Sever 1994). In assessing both reproductive and developmental hazards of workplace exposures increased attention must be paid to the possible effects among males.

It is quite likely that some defects of unknown aetiology involve a genetic component which may be related to parental exposures. Because of associations demonstrated between father’s age and mutation rates it is logical to believe that other paternal factors and exposures may be associated with gene mutations. The well-established association between maternal age and chromosomal non-disjunction, resulting in abnormalities in chromosomal number, suggests a significant role for maternal exposures in chromosomal abnormalities.

As our understanding of the human genome increases it is likely that we will be able to trace more developmental defects to mutagenic changes in the DNA of single genes or structural changes in portions of chromosomes.

Teratogenesis

The adverse effects on human development of exposure of the conceptus to exogenous chemical agents have been recognized since the discovery of the teratogenicity of thalidomide in 1961. Wilson (1973) has developed six “general principles of teratology” that are relevant to this discussion. These principles are:

1.    The final manifestations of abnormal development are death, malformation, growth retardation and functional disorder.

2.    Susceptibility of the conceptus to teratogenic agents varies with the developmental stage at the time of exposure.

3.    Teratogenic agents act in specific ways (mechanisms) on developing cells and tissues in initiating abnormal embryogenesis (pathogenesis).

4.    Manifestations of abnormal development increase in degree from the no-effect to the totally lethal level as dosage increases.

5.    The access of adverse environmental influences to developing tissues depends on the nature of the agent.

6.    Susceptibility to a teratogen depends on the genotype of the conceptus and on the manner in which the genotype interacts with environmental factors.

The first four of these principles will be discussed in further detail, as will the combination of principles 1, 2 and 4 (outcome, exposure timing and dose).

Spectrum of Adverse Outcomes Associated with Exposure

There is a spectrum of adverse outcomes potentially associated with exposure. Occupational studies that focus on a single outcome risk overlooking other important reproductive effects.

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Figure 9.1 [REP01FE] lists some examples of developmental outcomes potentially associated with exposure to occupational teratogens. Results of some occupational studies have suggested that congenital malformations and spontaneous abortions are associated with the same exposures—for example, anaesthetic gases and organic solvents.

Spontaneous abortion is an important outcome to consider because it can result from different mechanisms through several pathogenic processes. A spontaneous abortion can be the result of toxicity to the embryo or foetus, chromosomal alterations, single gene effects or morphological abnormalities. It is important to try to differentiate between karyotypically normal and abnormal conceptuses in studies of spontaneous abortions.

Timing of Exposure

Wilson’s second principle relates susceptibility to abnormal development to the time of exposure, that is, the gestational age of the conceptus. This principle has been well established for the induction of structural malformations, and the sensitive periods for organogenesis are known for many structures. Considering an expanded array of outcomes, the sensitive period during which any effect can be induced must be extended throughout gestation.

In assessing occupational developmental toxicity, exposure should be determined and classified for the appropriate critical period—that is, gestational age(s)—for each outcome. For example, spontaneous abortions and congenital malformations are likely to be related to first and second trimester exposure, whereas low birth weight and functional disorders such as seizure disorders and mental retardation are more likely to be related to second and third trimester exposure.

Teratogenic Mechanisms

The third principle is the importance of considering the potential mechanisms that might initiate abnormal embryogenesis. A number of different mechanisms have been suggested which could lead to teratogenesis (Wilson 1977). These include:

·       mutational changes in DNA sequences

·       chromosomal abnormalities leading to structural or quantitative changes in DNA

·       alteration or inhibition of intracellular metabolism, e.g., metabolic blocks and lack of co-enzymes, precursors or substrates for biosynthesis

·       interruption of DNA or RNA synthesis

·       interference with mitosis

·       interference with cell differentiation

·       failure of cell-to-cell interactions

·       failure of cell migrations

·       cell death through direct cytotoxic effects

·       effects on cell membrane permeability and osmolar changes

·       physical disruption of cells or tissues.

By considering mechanisms, investigators can develop biologically meaningful groupings of outcomes. This can also provide insight into potential teratogens; for example, relationships between carcinogenesis, mutagenesis and teratogenesis have been discussed for some time. From the perspective of assessing occupational reproductive hazards, this is of particular importance for two distinct reasons: (1) substances that are carcinogenic or mutagenic have an increased probability of being teratogenic, suggesting that particular attention should be paid to the reproductive effects of such substances, and (2) effects on deoxyribonucleic acid (DNA), producing somatic mutations, are thought to be mechanisms for both carcinogenesis and teratogenesis.

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Dose and Outcome

The fourth principle concerning teratogenesis is the relationship of outcome to dose. This principle is clearly established in many animal studies, and Selevan (1985) has discussed its potential relevance to the human situation, noting the importance of multiple reproductive outcomes within specific dose ranges and suggesting that a dose-response relationship could be reflected in an increasing rate of a particular outcome with increasing dose and/or a shift in the spectrum of the outcomes observed.

In regard to teratogenesis and dose, there is considerable concern about functional disturbances resulting from the possible behavioural effects of prenatal exposure to environmental agents. Animal behavioural teratology is expanding rapidly, but human behavioural environmental teratology is in a relatively early stage of development. At present, there are critical limitations in the definition and ascertainment of appropriate behavioural outcomes for epidemiological studies. In addition it is possible that low-level exposures to developmental toxicants are important for some functional effects.

Multiple Outcomes and Exposure Timing and Dose

Of particular importance with respect to the identification of workplace developmental hazards are the concepts of multiple outcomes and exposure timing and dose. On the basis of what we know about the biology of development, it is clear that there are relationships between reproductive outcomes such as spontaneous abortion and intrauterine growth retardation and congenital malformations. In addition, multiple effects have been shown for many developmental toxicants (Table 9.1 [REP01TE]).

Relevant to this are issues of exposure timing and dose-response relationships. It has long been recognized that the embryonic period during which organogenesis occurs (two to eight weeks post-conception) is the time of greatest sensitivity to the induction of structural malformations. The foetal period from eight weeks to term is the time of histogenesis, with rapid increase in cell number and cellular differentiation occurring during this time. It is then that functional abnormalities and growth retardation are most likely to be induced. It is possible that there may be relationships between dose and response during this period where a high dose might lead to growth retardation and a lower dose might result in functional or behavioural disturbance.

Male-Mediated Developmental Toxicity

While developmental toxicity is usually considered to result from exposure of the female and the conceptus—that is, teratogenic effects—there is increasing evidence from both animal and human studies for male-mediated developmental effects. Proposed mechanisms for such effects include transmission of chemicals from the father to the conceptus via seminal fluid, indirect contamination of the mother and the conceptus by substances carried from the workplace into the home environment through personal contamination, and—as noted earlier—paternal preconception exposures that result in transmissible genetic changes (mutations).

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