ABirth index = (number of oﬀspring born alive divided by the number of implantations); Bgestation index = (number of females with live oﬀspring divided by the number of pregnant females); n: number of dams per group. Table 9: Sperm parameters in control and high-dose male rats used as breeding males in the F0 and F1 two-generation reproduction study. Dose (mg/kg/day) Sperm HRS motility (%) (×106/g) Sperm count (cauda Abnormal epididymal) (×106/g) sperm (%) Types of abnormal sperm (%) no. Tailless sperm (%) 91.0 ± 4.5 83.73 ± 12.52 534.73 ± 72.79 0.81 ± 1.26 91.3 ± 3.2 83.64 ± 10.21 537.29 ± 66.92 0.33 ± 0.37 0.25 ± 0.04 ± 0.00 ± 0.42 ± 0.10 ± 0.62 0.14 0.00 0.76 0.40 0.04 ± 0.00 ± 0.00 ± 0.29 ± 0.00 ± 0.14 0.00 0.00 0.35 0.00 0 200 1000 2000 0 n n 0 n n 2000 2000 22.2 ± 0.4 n = 18 22.2 ± 0.4 n = 18 22.2 ± 0.4 n = 18 22.3 ± 0.6 n = 20 26 26 22 22 26 26 22 22 15.8 ± 1.2 n = 18 15.8 ± 2.5 n = 18 13.8 ± 4.1 n = 19 12.6 ± 4.7∗ n = 21 14.9 ± 1.9 n = 18 14.0 ± 2.3 n = 18 12.7 ± 3.9 n = 19 11.3 ± 5.1 n = 21 26 26 22 22 F0 generation F1 generation 26 26 21 22 Journal of Toxicology Table 8: Eﬀects of SE5-OH administration on F1 generation rat dam gestation and delivery parameters. Dose (mg/kg/day) Gestation length (days) Number of implantation sites Number of oﬀspring born alive Birth indexA (%) Gestation indexB (%) 86.0 ± 20.1 75.98 ± 17.86 551.21 ± 151.94 0.52 ± 0.83 86.7 ± 19.7 81.57 ± 14.31 557.51 ± 142.72 0.40 ± 0.71 0.31 ± 0.00 ± 0.00 ± 0.21 ± 0.00 ± 0.43 0.00 0.00 0.62 0.00 0.19 ± 0.00 ± 0.00 ± 0.21 ± 0.00 ± 5.18 ± 15.30 0.51 0.00 0.00 0.34 0.00 A: without hook, B: banana-like head, C: amorphous, D: folded in midpiece, E: others; HRS: homogenization-resistant spermatids; n: number of males per group. in the 2000 mg/kg/day F1 dams, but was not seen in the male rats. The increase at the 1000 mg/kg/day dose did not exceed the limits of 5% variability, which is generally considered within the accepted level of variability to the control rats. The relative liver weight at the 2000 mg/kg/day dose had greater than 5% variability from controls. There was a signiﬁcant increase in the absolute and relative thyroid weight in the 1000 mg/kg/day dose group, but this was not considered related to SE5-OH treatment, as this eﬀect was not noted in any other dose levels. The highest dose of SE5- OH (2000 mg/kg/day) had some indications of toxicity at the gestational and conception stages in the rat model. The adrenal cortex of F0 females at the 2000 mg/kg/day SE5-OH dose had an increased number of diﬀuse lipid droplets (4/10 in the high-dose group versus 0/10 in the controls) noted in the glomerular zone of the adrenal glands. Lipid droplets are the intracellular stores of cholesterol esters, precursors of hormones formed in the rat adrenal glands [47]. It has been documented that cell enlargement and widening of the zona glomerulosa of the adrenal cortex (associated with an increase in lipid droplet volume) may be induced via androgen receptor binding, and that isoﬂavones (including equol as an antiandrogen [48]) have been reported to alter androgen receptor expression and adreno- cortical function [49, 50]. However, the exact mechanism is not known, as isoﬂavones have been shown to increase or decrease androgen production, depending on the model used [51–54]. Wood et al. [53] noted that consumption of a soy protein providing 129 mg/day isoﬂavones (which provided approx. 31 mg daidzein per day) by female cynomolgus monkeys for 36 months did not alter serum androgen levels, but decreased adrenal weight (P < .0006). However, previous postmenopausal oral contraceptive administration abolished this eﬀect (P < .01). Diﬀuse lipid droplets in the adrenal cortex have been noted in the rat model as a consequence of advancing age [47], and coupled with pregnancy, they may have been a factor in the results of this study. The maximal plasma concentration was 390 ± 90 and 414 ± 32 ng/mL, respectively, for the S- and R- enantiomers. A 26 26 21 22 93.8 ± 7.4 n = 18 88.9 ± 9.2 n = 18 88.1 ± 22.8 n = 19 84.5 ± 24.8 n = 21 B 26 26 21 22 C 26 26 21 22 D 26 26 21 22 E 26 26 21 22 9 100 100 94.7 95.2 1.96 ± 2.03 1.81 ± 2.83 1.95 ± 1.77 26 26 21 22