Dioxin exposure, from infancy through puberty, produces endocrine disruption and affects human semen quality

Abstract

Background: Environmental toxicants are allegedly involved in decreasing semen quality in recent decades; however, definitive proof is not yet available. In 1976 an accident exposed residents in Seveso, Italy, to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Objective: The purpose of this study was to investigate reproductive hormones and sperm quality in exposed males.

Methods: We studied 135 males exposed to TCDD at three age groups, infancy/prepuberty (1-9 years), puberty (10-17 years), and adulthood (18-26 years), and 184 healthy male comparisons using 1976 serum TCDD levels and semen quality and reproductive hormones from samples collected 22 years later.

Results: Relative to comparisons, 71 men (mean age at exposure, 6.2 years; median serum TCDD, 210 ppt) at 22-31 years of age showed reductions in sperm concentration (53.6 vs. 72.5 million/mL; p = 0.025); percent progressive motility (33.2% vs. 40.8%; p < 0.001); total motile sperm count (44.2 vs. 77.5 x 10(6); p = 0.018); estradiol (76.2 vs. 95.9 pmol/L; p = 0.001); and an increase in follicle-stimulating hormone (FSH; 3.58 vs. 2.98 IU/L; p = 0.055). Forty-four men (mean age at exposure, 13.2 years; median serum TCDD, 164 ppt) at 32-39 years of age showed increased total sperm count (272 vs. 191.9 x 10(6); p = 0.042), total motile sperm count (105 vs. 64.9 x10(6); p = 0.036), FSH (4.1 vs. 3.2 UI/L; p = 0.038), and reduced estradiol (74.4 vs. 92.9 pmol/L; p < 0.001). No effects were observed in 20 men, 40-47 years of age, who were exposed to TCDD (median, 123 ppt) as adults (mean age at exposure, 21.5 years).

Conclusions: Exposure to TCDD in infancy reduces sperm concentration and motility, and an opposite effect is seen with exposure during puberty. Exposure in either period leads to permanent reduction of estradiol and increased FSH. These effects are permanent and occur at TCDD concentrations < 68 ppt, which is within one order of magnitude of those in the industrialized world in the 1970s and 1980s and may be responsible at least in part for the reported decrease in sperm quality, especially in younger men.

Keywords: TCDD; dioxin; endocrine disruption; environmental contaminants; human sperm quality; reproductive hormones.

Figure 1

Flow chart of study showing the relationship between eligible men in 1976, participant men in 1998, and the comparison group on the effects of exposure to TCDD at different ages (1–9; 10–17; 18–26 years) on reproductive hormones and semen quality. Values in parentheses indicate the percentage of men respective to the eligible ones. ^aMedian TCDD serum concentration in 1976 (ppt on a serum lipid basis). ^bVery highly exposed men (> 2,000 ppt) were excluded: 10 men who were 1–9 years old in 1976 and 6 men who were 10–17 years old in 1976, with median serum concentrations of 6,350 ppt and 3,700 ppt, respectively; none of the men exposed at 18–26 years of age was exposed to > 2,000 ppt TCDD. ^cFor information about this group, see Table 1. ^dSerum TCDD concentrations for the comparison groups were assumed to be ≤ 15 ppt in 1976 and < 6 ppt in 1998. ^eValues in parentheses indicate compliance of the comparison group.

Figure 2

Box plots showing dioxin concentration on a serum lipid basis (A,C) and body burden [ng/kg body weight (bw); B,D] in the same men in 1976 (A, B) and in 1998 (C, D). Values shown are median (line within box), 25th and 75th percentiles (bottom and top of box, respectively), and outliers (circles). Whiskers indicate values within 1.5 times the interquartile range (25th–75th percentiles), and values in parentheses indicate number of men. Serum dioxin concentrations in comparison groups were < 15 ppt in 1976 and < 6.0 ppt in 1998. Because weight was not available in medical records for most of the subjects, dioxin body burden was mostly derived in 1976 using normal percentile distribution of weight according to age.

Figure 3

TCDD quartile distribution (adjusted mean and 95% confidence interval) of sperm concentration (A, B), total motile sperm count (C, D), and serum E₂ (E, F) for exposed men and of same-age comparison groups [A,C,E; men who were 1–9 years of age in 1976 (22–31 years of age in 1998); B,D,F; men who were 10–17 years of age in 1976 (32–39 years of age in 1998). Median concentrations of TCDD quartiles (shown in parentheses) are expressed as parts per trillion on a serum lipid basis in 1976.