Hormonally Active Agents in the Environment (1999) / Chapter Skim
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5 Effects on Reproduction and Development
5 Effects on Reproduction and Development
Pages 119-170
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From page 119... ...
affects animals and humans similarly is not clear, but because exposure of animals to DES causes alterations in male and female offspring, the possibility must be considered that there will be adverse effects from exposure to other compounds with estrogenic, antiestrogenic, or antiandrogenic activity. There are also concerns that exposure to low doses of certain chemicals at critical stages in organ development can result in abnormalities that lead to irreversible changes in the functioning of organ systems later in life.
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From page 120... ...
Effective doses may be lower than effective doses in adults, and the effects are considerably removed in time from the exposure, which can make causal relationships more difficult to establish. This chapter is a critical analysis of the literature on the link between exposure to HAAs and reproductive and developmental effects observed in laboratory studies, in humans, and in wildlife populations.
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From page 121... ...
Male offspring from pregnant rats fed 100 mg/kg/d p,p'-DDE, the antiandrogenic metabolite of DDT, on gestation d 14-18 had reduced anogenital distance and had nipples (androgen normally blocks nipple retention in male rodents) (Kelce et al.1995~.
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From page 122... ...
Administration of 50 mg/kg/d methoxychlor to female rats throughout pregnancy and lactation resulted in smaller testes, epididymides, and reduced sperm count in male offspring (Gray et al.1989; Gray 1992~. The mechanism by which methoxychlor affects the reproductive system and reproductive behavior of laboratory animals is not understood.
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From page 123... ...
When a 15-mg/kg/d dose of chlordecone was fed to pregnant rats on d 14-20 of gestation, 12 of 21 female offspring developed persistent vaginal estrus; the other nine rats were anovulatory at 6 mo of age (Gellert and Wilson 1979~. The effects were consistent with those seen after exposure to estrogen, but no estrogenic effects were observed among male offspring.
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From page 124... ...
PCBs during gestation, female offspring had delayed vaginal opening and male offspring had significantly reduced absolute and relative testis weight (Lundkvist 1990~. Pre- and postnatal exposure to coplanar PCBs can modulate thyroid hormone concentrations and uptake.
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From page 125... ...
1998~. In addition to reproductive effects, prenatal exposure to PCBs has been shown to cause deficits in neurodevelopment, such as impaired learning and altered activity levels in rats fed PCB-contaminated fish (Tilson et al.
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From page 126... ...
Ovarian weight was significantly reduced. In male offspring, the same treatment on gestation d 15 caused delayed puberty and reductions in ejaculated and epididymal sperm counts and in sex accessory gland size (Gray et al.
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From page 127... ...
In addition, 2 ,ug/kg/d bisphenol A produced significant enlargement of the preputial glands in male offspring, whereas the epididymides were significantly reduced. A dose of 20 ,ug/kg/d bisphenol A reduced daily sperm production per gram of testis by 20%, while daily sperm production uncorrected for testis weight was not significantly different (vom Saal et al.
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From page 128... ...
There were significant decreases in absolute testis weight, in the ratio of testis-to-kidney size, in relative ventral prostate weight, and in daily sperm production in male offspring exposed to 1,000,uglL octylphenol, and there was a significant reduction in relative prostate weight at both concentrations. When male offspring were treated postnatally only with 1,000 ,uglL octylphenol on d 1-22 after birth, there was a significant reduction in average and relative testis weight (Sharpe et al.
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From page 129... ...
When 1,000,uglL BBP was administered in drinking water to female rats before mating and throughout lactation (nominal intake based on water intake ranged from 126 ,ug/kg/d in the first 2 d after birth to 366,ug/kg/d just before weaning) , there was a small but significant reduction in mean testicular size and a reduction in daily sperm production in male offspring at d 90-95 (Sharpe et al.
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From page 130... ...
At necropsy, the high-dose Fit males were found to have significantly reduced epididymal sperm counts and testicular spermatid head counts. Eight of the 10 males had degenerated seminiferous tubules and five had underdeveloped or otherwise defective epididymides.
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From page 131... ...
They showed that when pregnant rats were fed DBP on d 11-21 of pregnancy at an average daily intake of 555 and 661 mg/kg, there was a significant incidence of undescended testes and a significant decrease in anogenital distance in male fetuses. HUMAN STUDIES DDT and its Metabolites In a study of 722 women from North Carolina, Rogan et al.
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From page 132... ...
No significant increases in risk for fetal death were found in regard to lifetime estimates of PCB exposure based on species-specific PCB levels, the number of years of fish consumption, kilograms of sport fish consumed between 1990-1991, and a lifetime estimate of kilograms eaten. Studies are being conducted to determine the effects of fish consumption on the reproductive health of a cohort of Michigan anglers (Courval et al.1996a)
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From page 133... ...
However, in samples with a low sperm count (<20 mil/mL) , sperm motility was inversely associated with 3 PCB congeners (2,4,5,2',4',5'-hexachlorobiphenyl, p = 0.002, SE = 26; 2,4,5,3',4'- pentachlorobiphenyl, p = 0.002, SE = 20; and 2,4,5,2',3',4'hexachlorobiphenyl, p < 0.01, SE = not provided)
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From page 134... ...
The investigators concluded that the magnitude of the effects was small compared with other known determinants of gestational age and birth weight, and the biologic importance of these effects was likely to be negligible. In the North Carolina Breast Milk and Formula project, 912 children were followed to investigate the effects of prenatal exposure to environmental levels of PCBs and DDE from maternal breast milk (Rogan et al.
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From page 135... ...
Collectively, the data on prenatal exposure to high levels of PCBs from the Yusho and Yu-Cheng incidents and studies from the United States and the Netherlands of prenatal exposure to PCBs from maternal diet indicate that PCBs can affect birth weight and growth. Lower birth weights were not observed in the North Carolina cohort, but that might be explained by the lower exposure level of this cohort compared with the others.
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From page 136... ...
1983) , thyroid hormone concentrations were measured in the blood of Dutch infants exposed to elevated concentrations of dioxin in breast milk (Pluim et al.
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From page 137... ...
Using regression models, the investigators found that testosterone concentrations in serum decreased with increasing TCDD exposure (slope = -0.4276, standard error = 0.0950~. When adjustments were made for possible confounders, the slopes changed with military occupation.
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From page 138... ...
, and effects on fertility and development. Positive correlations have been found in some studies, and these are presented below to illustrate some of the reproductive and developmental effects observed among people exposed to agricultural chemicals.
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From page 139... ...
Studies with laboratory animals have shown that prenatal exposure to some HAAs, such as methoxychlor (Gray et al.
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From page 140... ...
However, their data do not directly address the question of a change in rate of the defect; 1990 New York births were not compared with births in New York in the 1950s, when rates might well have been lower. With regard to hypospadias, cryptorchidism, testicular cancer, and sperm count, there is considerable evidence for geographic variation.
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From page 141... ...
wrote, "The overall decrease in the sperm concentration and the semen volumes would tend to incriminate an environmental factor to which the entire population has been exposed." In 1979, Macleod and Wang noted that several studies on fertile males found a "marked reduction in spermatogenesis since 1951." These authors' analysis of their own historical data of infertile populations, however, did not support a decline. In 1980, James conducted a multinational analysis of 29 studies of sperm concentration published over 45-yr and concluded, "There can be no reasonable doubt that these reported mean sperm counts show a decline with time of publication, at least since 1960." Dougherty et al.
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From page 142... ...
"Local trend studies," on the other hand, examine data within a single country or state to assess trends in sperm concentration. While many local and multinational trend studies include data on multiple parameters; all provide data on trends in sperm concentration, the parameter for which methods have remained most comparable over time.
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From page 143... ...
Their multiple-regression analyses considerably improved model fit. For example, the adjusted R2 was .80 for the linear multiple-regression model compared with .36 for the simple linear model.
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From page 144... ...
Although it was noted that the method used to determine sperm counts overestimated sperm concentrations, the authors judged that it did not affect the conclusion that there was no change over time.1 In a study conducted in Australia using potential sperm donors, Handelsman (1997) found no significant difference in sperm concentration over time (1980-1995)
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From page 145... ...
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From page 146... ...
indirectly examined the relationship between sperm concentration and fertility by comparing time to pregnancy between Finland (high to normal sperm counts) and Britain (low sperm counts)
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From page 147... ...
Immature male rainbow trout and common carp were placed in cages in the effluent stream of 15 sewage treatment plants throughout southern England and Wales (Purdom et al.
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From page 148... ...
Studies at other locations outside of England have confirmed the observation that male fish exposed to STPE exhibit elevated plasma concentrations of vitellogenin. In a study of male common carp from five riverine locations in Minnesota, elevated plasma vitellogenin and depressed plasma testosterone concentrations were observed in fish collected from 1 location, an effluent channel below a metropolitan sewage treatment plant on the Mississippi River (Folmar et al.
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From page 149... ...
It should be noted that a syndrome similar to that observed in the chinook salmon was found in coho salmon fry reared in Michigan during the late 1960s and was attributed to residues of DDT in coho salmon eggs (Johnson and Pecor 1969~. Based on laboratory studies of different fish species, the concentration of DDT that is lethal to salmonid eggs is estimated at 1.0-10 mg/kg, wet weight (ww)
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From page 150... ...
When total concentrations of PCBs in fish and fish eggs from the Great Lakes were examined and compared with the results from controlled laboratory studies, the calculated hazard indices indicated that concentrations of these residues were probably sufficient to have caused egg and fry mortality (Willford et al. 1969; Halter and Johnson 1974; Lidman et al.
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From page 151... ...
These include reduced egg-survival-to-hatch rates, depressed steroidogenesis, lowered plasma concentrations of steroids and pituitary hormones in males and females, and lowered egg thyroid hormone concentrations. Another reproductive abnormality is the increased incidence of embryonic teratogenesis.
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From page 152... ...
Follicles from fish exposed to BPME had a decrease in basal secretion of testosterone and 17-20-progesterone and a reduced response to either hCG or Forskolin (Van Der Kraak et al.
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From page 153... ...
However, basal testosterone was not significantly different from controls (MacLatchy and Van Der Kraak 1995~. Those data indicate that synthetic and natural HAAs released from paper mills that process raw wood products can alter the reproductive physiology of fish.
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From page 154... ...
. For example, the action of exogenous corticosterone on toads has been shown to closely resemble the effects of exogenous thyroid hormones, suggesting that steroids might interact with endogenous thyroid hormones (Hayes et al.
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From page 155... ...
(1991) identified high concentrations of various persistent pesticides and their metabolites in alligator eggs collected between 1984 and 1985 from Lake Apopka (Table 5-2~.
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From page 156... ...
1994~. Follow-up studies of juvenile alligators from Lake Apopka and the reference lake indicate that some oocytes are multinucleated in females from the control group, but polyovular follicles were not seen in any of the control females (Pickford 1995~.
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From page 157... ...
Egg viability on Lake Apopka has averaged less than 20% since the mid-1980s, and embryonic death occurs mainly at the zygote to late gastrula stage (Masson 1995~. Additional work is needed to determine the causes and the significance of polyovular follicles in wild populations of alligators.
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From page 158... ...
Most female alligators exhibited normal secondary sex characteristics at the gross morphologic level. However, a few individuals on Lake Apopka had hypertrophied clitorises (Guillette et al.
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From page 159... ...
1995~. As described for the alligator eggs collected from Lake Apopka (Masson 1995)
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From page 160... ...
1993; Fox 1992~. The studies of interest have shown alterations in sexual behavior, abnormal reproductive morphology, severe developmental abnormalities associated with growth and metabolism, and eggshell thinning.
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From page 161... ...
In general, femalefemale associations in gull colonies are believed to occur when there is a relative shortage of breeding male gulls available. Experimental manipulation of sex ratios in gull colonies by selectively removing males from stable colonies has demonstrated that sex ratio skew alone is sufficient to cause a proportion of the excess females to pair (Conover and Hunt 1984b)
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From page 162... ...
The observations that the colonies most affected were in areas of great DDT contamination and that a few DDT congeners have produced abnormal gonadal development in laboratory studies support the hypothesis that environmental contaminants may have played a role in the sex ratio skew. Alterations in Behavior Behavioral abnormalities observed in the wild include aberrant parental behaviors, such as less inclination to sit on eggs or to defend nests, which was observed in herring gulls in Lake Ontario (Fox et al.
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From page 163... ...
Thus, there is evidence from laboratory studies that environmental contaminants in the Great Lakes region could cause behavioral anomalies in breeding synchrony, nest construction, incubation attentiveness, and parental care at ambient concentrations but these effects are not necessarily attributable to their hormonal activities.
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From page 164... ...
found in the eggs of wild gulls caused effects consistent with those induced by estradiol and DES (Fry and Toone 1981) , it is plausible that DDT or other estrogenic contaminants could be responsible for the effects observed in the wild.
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From page 165... ...
l991~. Adults from populations in which chicks have GLEMEDS have shown abnormal plasma thyroid hormone concentrations and thyroid morphology (Fox 1992)
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From page 166... ...
However, it does not appear that eggshell thinning is a result of DDE acting as a hormone-receptor agonist or antagonist. The situation is complicated further because sensitivities to DDE-induced eggshell thinning vary among avian species, suggesting that different mechanisms cause eggshell thinning in different species.
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From page 167... ...
Laboratory studies using male and female rats, mice, and guinea pigs, and female rhesus monkeys have shown that exposure of these animals during development to certain HAAs (e.g., DDT, methoxychlor, PCBs, dioxin, bisphenol A, octylphenol, BBP, DBP, chlordecone, and vinclozolin) can produce structural
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From page 168... ...
Collectively, these studies indicate that prenatal exposure to PCBs can cause lower birth weight and shorter gestation, and have also been correlated with IQ and memory deficits as well as delayed neuromuscular development. Pre- and post-natal exposure to PCBs and PCDFs from accidental contamination of rice oil in Yusho, Japan and Yu-Cheng, Taiwan have resulted in various developmental defects.
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From page 169... ...
Finally, B-sitosterol found in paper-mill effluent has been shown to alter the reproductive physiology of goldfish under experimental conditions. Laboratory studies are also consistent with some reproductive and developmental abnormalities (e.g., skewed sex ratios, behavioral modifications, and morphologic abnormalities of the gonads)
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From page 170... ...
Regional differences in male reproductive end points such as sperm count and rates of hypospadias, cryptorchidism, and testicular cancer should be examined prospectively to determine whether the differences can be associated with genetic and environmental factors. Such prospective analyses should be accompanied by quantitative sensitivity analyses.
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