Interpretation of studies on the developmental reproductive toxicology of 2,3,7,8-tetrachlorodibenzo-p-dioxin in male offspring

Abstract

There have been several studies on the maternal administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and effects in the reproductive tract of male offspring, subsequent to risk assessments undertaken in 2001. This review compares the methodology and results to examine key methodological features, and consistency in reported outcomes. Maternal dosing at >0.8 microg TCDD/kg causes lethality and weight loss, and it is difficult to distinguish between direct and indirect effects of TCDD at these dose levels. Statistically significant effects of maternal doses of <1 microg TCDD/kg (i.e. the dose levels relevant for risk assessment) on prostate weight or epididymal sperm counts in offspring were reported in the minority of studies. The pharmacokinetics of TCDD differs considerably between acute and chronic dosing, and with dose level of TCDD. On the basis of body burden, TCDD had different potency at inducing adverse effects in the only comparison study between acute and chronic dosing. Understanding of the pharmacokinetics of TCDD and relationship to adverse effects in offspring is required. These analyses identify key features of TCDD developmental toxicity in male offspring, and identify data needs for future risk assessment.

Fig. 1. Male reproductive effects of TCDD after developmental administration

A. Some of the effects noted by Mably et al (1992). Holtzman rats were dosed on GD15 with the indicated dose of TCDD (ng/kg), and daily sperm production (circle), right epididymis weight (star), ventral prostate weight (square), seminal vesicle weight (diamond) and cauda epididymal sperm number (triangle) measured in the F₁ males on PND 63 (open symbols) or PND120 (closed symbols). Results are normalised to control (set as 100%), and are presented as mean and SD. * indicates P<0.05; note that at 64 ng/kg, right epididymis weight, seminal vesicles weight and ventral prostate weight are not significantly different from control. B. Comparison of effects of TCDD on F1 males at PND62-70, for a maternal TCDD dose of approximately 500 ng/kg and below. Data from (Mably et al., 1992c), (Mably et al., 1992a), (Faqi et al., 1998), (Gray et al., 1997) and (1996) (Wilker et al., 1996) are compared, on the basis of stated statistically significant results. √ means that there was a statistically significant effect. No means no statistically significant effect, Not Done means that the measurement is not reported, and ¹ refers to measurements on whole prostate, rather than ventral prostate weight.

Fig. 2. Maternal pharmacokinetics of TCDD

A. The liver: adipose tissue TCDD concentrations from each animal in (Bell et al., 2007b) (Acute study; open symbols) and (Bell et al., 2007c) (Chronic study; filled symbols) were calculated from (Bell et al., 2007a). Data are presented as mean ± SD, for week 10 of dosing (square), week 12 (diamond) GD16 (triangle) and GD21 (circle). B. Relative proportion of TCDD dose in a tissue was calculated as described in materials and methods for the acute study (Bell et al., 2007b). GD16 samples are open symbols, GD21 samples are closed symbols. Liver is shown by circles, adipose by triangles, blood by squares and fetus by diamonds. C. As for B, but for the chronic study (Bell et al., 2007c). Week 10 samples are shown in light grey, and week 12 samples are in dark grey. D. Effect of dose on apparent half-life of TCDD. Data are taken from (Bell et al., 2007a, Bell et al., 2007c), apparent half-life calculated as described in materials and methods, and plotted against dose. The values shown are mean plus an indication of variance, derived from the SD of body burden of TCDD. Data are from week 10 (circle), week 12 (square), GD16 (triangle) or GD21 (inverted triangle). E. As for D, but using the data from (Hurst et al., 2000a). Data are from GD9 (star), GD16 (triangle), GD21 (inverted triangle) and PND4 (circle). F. Effect of dose on apparent half-life of TCDD in mice. As for D, but the data are taken from (Diliberto et al., 2001).

Fig. 3. Effect of developmental exposure to TCDD on male F1 reproductive endpoints

A. Effects on prostate weight at PND 62–70. All experiments are normalised to control values of 100%, and results are shown as mean ± SD. Statistical significance at P<0.05 is shown by filled symbols. Data are from (Mably et al., 1992c) (circle), (Gray et al., 1997) (triangle), (Faqi et al., 1998) (circle with cross), (Simanainen et al., 2004) lines A (square), B (square with dot) and C (square with cross), (Yonemoto et al., 2005) (diamond with cross), (Ohsako et al., 2002) (diamond), (Wilker et al., 1996) (inverted triangle), (Bell et al., 2007b) (hexagon), and (Bell et al., 2007c) (hexagon with cross). Results are ventral prostate weight, except for (Bell et al., 2007b), (Wilker et al., 1996) and (Faqi et al., 1998), which are prostate weight. Doses greater than 1 μg TCDD/kg are not shown. Studies with chronic dosing of TCDD are shown by the equivalent acute doses, based on tissue concentrations of TCDD (Bell et al., 2007a). B. Effects on prostate weight at PND 120+. All experiments are normalised to control values of 100%, and results are shown as mean ± SD. Statistical significance at P<0.05 is shown by filled symbols. Data are from (Mably et al., 1992c) (circle), (Gray et al., 1997) (triangle), (Faqi et al., 1998) (circle with cross), (Ikeda et al., 2005) (square), (Ohsako et al., 2001) (diamond), (Bell et al., 2007b) (hexagon), and (Bell et al., 2007c) (hexagon with cross). Results are ventral prostate weight, except for (Bell et al., 2007b) and (Faqi et al., 1998), which are prostate weight. C. Effects on epididymal sperm count at PND 62–70. All experiments are normalised to control values of 100%, and results are shown as mean ± SEM. Statistical significance at P<0.05 is shown by filled symbols. Data are from (Mably et al., 1992a) (circle), (Gray et al., 1997) (triangle), (Faqi et al., 1998) (circle with cross), (Simanainen et al., 2004) lines A (square), B (square with dot) and C (square with cross), (Yonemoto et al., 2005) (diamond with cross), (Ohsako et al., 2002) (diamond), (Wilker et al., 1996) (inverted triangle), (Bell et al., 2007b) (hexagon), and (Bell et al., 2007c) (hexagon with cross). Doses greater than 1 μg TCDD/kg are not shown. Studies with chronic dosing of TCDD are shown by the equivalent acute doses, based on tissue concentrations of TCDD (Bell et al., 2007a). D. Effects on epididymal sperm counts at PND 120+. All experiments are normalised to control values of 100%, and results are shown as mean ± SEM. Statistical significance at P<0.05 is shown by filled symbols. Data are from (Mably et al., 1992c) (circle), (Gray et al., 1997) (triangle), (Faqi et al., 1998) (circle with cross), (Ikeda et al., 2005) (square), (Ohsako et al., 2001) (diamond), (Bell et al., 2007b) (hexagon), and (Bell et al., 2007c) (hexagon with cross).