Spermatogenesis and Fertility adapted from Creasy 1997

There are a large number of structurally diverse chemicals that cause testicular damage in laboratory animals, but the effects of only relatively few have been proven in humans. The most meaningful studies have been performed with di-

bromochloropropane (DBCP), which compromises male fertility, but it has long been known to induce testicular atrophy in rats.

A number of regulatory guidelines for studies on reproduction and fertility exist. For drug registration, the results of the International Conference on Harmonization (ICH) have been accepted by the governments of the United States, the European Union and Japan. For male reproductive toxicity, the guidelines require a premating dosage for at least 4 weeks, and an evaluation of testicular histology after fixation with Bouin's solution and staining with PAS (periodic acid Schiff). The guidelines do not include two-generation studies, which would probably be useful for the detection of oestrogenic effects; these are recommended by guidelines of the Environmental Protection Agency (EPA) and the Organization for Economic Co-operation and Development (OECD).

A testicular toxicant will usually result in germ cell loss. This is easy to verify because of histological observation. Also, germ cell degeneration, which produces different features in different generations of spermatogenic cells, may be observed. The particular event of delayed spermia-tion is more difficult to detect. It can be observed only when the stages of the spermatogenetic cycle are specifically evaluated. Sertoli cells and Leydig cells may also be affected.

As a practical approach for the assessment of testicular damage, the following qualitative measures are recommended:

1. Check which are the most differentiated form of germ cells, i.e. spermatogonia or spermatocytes.

2. Check for inhibited sperm release.

3. Check for disorganization of the normal spermatogenic stages.

4. Look for an increased number of abnormal cells.

5. Check the epididymis for cell changes of spermatozoa.

As quantitative parameters, the following measurements can be acquired:

1. Tubular diameter

2. Cell counts of spermatocytes or other cells, expressed as a ration to Sertoli cell number

3. Counting homogenization-resistant spermatids (which is the most rapid and sensitive method)

A particular question concerns the genetic transfer of sperm abnormalities to the offspring. More than 100 chemicals which induce detrimental effects to sperm-parameter quality were known by 1983 (Wyborek et al. 1983). It is likely that these substances are also able to induce numerical and structural chromosomal defects or even single-gene defects.

Table 1.1.1 DNA and chromosomal alterations that can be transmitted by sperm (from Wyborek et al. 2005)

Aneuploidy Of sex chromosomes Of autosomes Structural aberrations Duplications/deletions Rearrangements Chromosome breaks Epigenetic modifications Imprinting

Premutational lesions DNA adducts Protamine adducts Single- and double-strand breaks Nucleotide Gene mutations

The possible genomic alterations are listed in Table 1.1.1 Alterations of the genome of the postmeiotic, haploid cells may be transported to the zygotes. In human sperm, transient increased chromosomal abnormalities were observed by FISH within the first months after chemotherapy with antineoplastic drugs. The knowledge of the mechanisms underlying the alterations is limited, since only few compounds have been tested sufficiently. It is also unknown which drugs produce transient, and which produce possibly permanent, alterations of maturing germ cells.

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