Induction of sperm head abnormalities by incorporated radionuclides: dependence on subcellular distribution, type of radiation, dose rate, and presence of radioprotectors

Abstract

In contrast to the biological effects caused by exposure to external beams of radiation, the effects of tissue-incorporated radionuclides are highly dependent on the type of radiation emitted and on their distribution at the macroscopic, microscopic, and subcellular levels, which are in turn determined by the chemical nature of the radionuclides administered. Induction of abnormalities of sperm heads in mice is investigated in this work after the injection of a variety of radiochemicals including alpha emitters. When the initial slopes of the dose-response curves are used to compare the relative biological effectiveness (RBE) of different radiocompounds, the alpha particles emitted in the decay of 210Po are more effective than Auger electrons emitted by 125I incorporated in the DNA of the spermatogonial cells, and both emissions are more effective than X rays. It is also shown that the Auger emitters (125I, 111In) distributed in the cell nucleus are more efficient in producing abnormalities than the same radionuclides localized in the cytoplasm. These findings are consistent with our earlier observations, where spermatogonial cell survival is assayed as a function of the testicular absorbed dose. Further, chronic irradiation of testis with gamma rays from intratesticularly administered 7Be is about three times more effective in causing abnormalities than a single acute exposure to 120-kVp X rays. The resulting RBE values correlate well with our data on sperm head survival with the same radiocompounds. Finally, the radioprotector cysteamine, when administered in small, nontoxic amounts, significantly reduces the incidence of sperm abnormalities from alpha-particle radiation as well as emissions from 125I incorporated into DNA, the dose reduction factors being 10 and 14, respectively.

FIG. 1

Biological clearance of the radiochemicals from mouse testes after intratesticular injection. The remaining fraction of initially injected activity is shown as a function of postinjection time for ⁷Be-chloride (solid triangles) and H¹²⁵IPDM (open circles).

FIG. 2

Dependence of induction of abnormal sperm heads on subcellular distribution of Auger-electron-emitting radionuclides in mouse testis. The percentage of sperm expressing abnormalities in head shape is shown as a function of the average absorbed dose from intratesticular decays of the radionuclide. The dose-response curves for ¹¹¹In-citrate (solid squares) and ¹¹¹In-oxine (open squares) are given in Fig. 2A. Those for H¹²⁵IPDM (open circles) and ¹²⁵IUdR (open diamonds) are given in Fig. 2B. The low-dose portion of the dose–response curves appears as an inset. The data are fitted by least squares to obtain the initial slope. The dependence of the response on the chemical nature of the compound, which in turn determines the subcellular distribution of the radionuclide, is clearly demonstrated in both cases. Intranuclear localization of ¹¹¹In and ¹²⁵I (¹¹¹In-oxine, ¹²⁵IUdR) produces significantly more abnormalities than when the same radionuclides are localized in the cytoplasm (¹¹¹In-citrate, H¹²⁵IPDM). Standard errors are shown.

FIG. 3

Comparison of a DNA-bound Auger-electron emitter (¹²⁵I) with an α emitter (²¹⁰Po) in causing abnormalities in sperm shape. The percentage of abnormal epididymal sperm is shown as a function of the testicular absorbed dose for ¹²⁵IUdR (open diamonds) and ²¹⁰Po-citrate (inverse open triangles). Error bars represent the standard error. An enlargement of the low-dose region of the curve is illustrated in the upper right corner. The efficacy of these radiochemicals in inducing abnormalities at very low doses is indicated by the large initial slopes (see Table I). Based on the initial slopes, the α particles emitted by ²¹⁰Po are about four times more effective in producing sperm abnormalities than the dense shower of Auger electrons emitted by DNA-bound ¹²⁵I.

FIG. 4

Relative efficacy of chronic versus acute irradiation of mouse testis with low-LET photons. Chronic irradiation is delivered to the testis by injecting ⁷Be-chloride (solid triangles) which emits 477-keV γ rays. Selective acute irradiation of the testis is accomplished using 120-kVp X rays (open triangles). The standard errors are shown. As indicated by the dose–response curves, induction of sperm abnormalities by chronic irradiation of the testis with intratesticularly localized ⁷Be is about three times more effective than acute X rays.

FIG. 5

Radioprotection provided by nontoxic amounts of intratesticularly administered cysteamine (MEA) against the effect of radionuclides incorporated into mouse testis. Figure 5A shows the mitigating effect of MEA against the Auger cascade electrons from DNA-bound ¹²⁵I. The open and solid diamonds represent ¹²⁵IUdR alone and ¹²⁵IUdR + MEA, respectively. Similarly, Fig. 5B illustrates the protective effect of MEA against 5.3-MeV α particles from ²¹⁰Po: ²¹⁰Po-citrate alone is represented by the open inverse triangles and ²¹⁰Po-citrate + MEA by the solid inverse triangles. Standard errors are given. Significant radioprotection is realized for both types of radiation, the dose reduction factors, based on the initial slopes (see inset), being 14 and 10 for ¹²⁵IUdR and ²¹⁰Po-citrate, respectively.

FIG. 6

Correlation of spermatogonial cell killing and induction of sperm shape abnormalities in mouse testes with incorporated radiochemicals. For all the radiocompounds, the relative biological effectiveness (RBE) is obtained by comparing their effects with those of acute 120-kVp X rays. For RBE values greater than 1, there is a linear relationship between the two experimental end points.