Spermatotoxicity of dibromoacetic acid in rats after 14 daily exposures

doi:10.1016/0890-6238(94)90009-4

Reproductive Toxicology

Volume 8, Issue 3, May–June 1994, Pages 251-259

https://doi.org/10.1016/0890-6238(94)90009-4 Get rights and content

Abstract

Halogenated acetic acids are major disinfection by-products of water chlorination and ozonation. Limited data in experimental animals indicate that repeated doses of dichloroacetic acid (DCA) or single doses of dibromoacetic acid (DBAA) cause testicular damage. In the present study, spermatotoxic effects were investigated in rats given oral doses of 0, 10, 30, 90, or 270 mg DBAA/kg/day for 14 days. In rats dosed with 270 mg/kg/day, there were marked effects on epididymal sperm motility and morphology including the flagellar fusion of 2 or more sperm. Testis weight, epididymis weight, and testicular sperm head counts were mildly reduced relative to control, whereas epididymal sperm counts were substantially decreased. Histologic changes in the tests included retention of Step 19 spermatids in Stages IX to XII, abnormal development of late spermatids, and the formation of atypical structures resembling residual bodies that were observed predominantly in Stages X to XIV and I of the cycle of the seminiferous epithelium. At the dosage of 90 mg/kg/day, effects on spermiation, spermatid development, epididymal sperm counts, sperm motility, and sperm morphology were less severe than at the higher dosage. Reduced caput sperm counts and mild effects on spermiation also occurred at 30 and 10 mg/kg/day. These studies indicate that subchronic exposure to DBAA has the potential to affect reproductive outcome in the rat. Compared to previous studies of DCA (12), DBAA, on a molar basis, appears to be a stronger testicular toxicant than the dichloro analogue.

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Disinfection byproducts (DBPs) are a class of ubiquitous chemicals in drinking water and inevitably result in widespread human exposures. Potentially adverse health effects of DBP exposures, including reproductive and developmental outcomes, have been increasing public concerns. Several reviews have focused on the adverse pregnancy outcomes of DBPs. This review summarized current evidence on male reproduction health upon exposure to DBPs from toxicological and epidemiological literature. Based on existing experimental studies, there are sufficient evidence showing that haloacetic acids (HAAs) are male reproductive toxicants, including reduced epididymal weight, decreased semen parameters and sperm protein 22, and declined testosterone levels. However, epidemiological evidence remains insufficient to support a link of DBP exposures with adverse male reproductive outcomes, despite that blood and urinary DBP biomarkers are associated with decreased semen quality. Eight potential mechanisms, including germ/somatic cell dysfunction, oxidative stress, genotoxicity, inflammation, endocrine hormones, folate metabolism, epigenetic alterations, and gut microbiota, are likely involved in male reproductive toxicity of DBPs. We also identified knowledge gaps in toxicological and epidemiological studies to enhance future needs.
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Method to assess component contribution to toxicity of complex mixtures: Assessment of puberty acquisition in rats exposed to disinfection byproducts
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Citation Excerpt :
In the F1 generation, the authors reported no significant differences in age at PPS or VO in any dose group (p > 0.05). We note that other published reports on the effects of DBPs either on additional reproductive/developmental endpoints in S-D rats or in other in vivo experimental models (examples include the reported effects of bromochloroacetic acid, dichloroacetic acid and dibromoacetic on sperm in S-D rats (Klinefelter et al., 2002; Linder et al., 1994a, 1994b, 1997a, 1997b) are not reported here, as we focused on puberty attainment in the S-D rat. Narotsky et al. (2015) administered the DM, comprised of nine regulated DBPs, as drinking water to pregnant rats from GD 0 through weaning of their offspring; treatment of the F1 generation via drinking water continued to the end of the study.
A method based on regression modeling was developed to discern the contribution of component chemicals to the toxicity of highly complex, environmentally realistic mixtures of disinfection byproducts (DBPs). Chemical disinfection of drinking water forms DBP mixtures. Because of concerns about possible reproductive and developmental toxicity, a whole mixture (WM) of DBPs produced by chlorination of a water concentrate was administered as drinking water to Sprague–Dawley (S–D) rats in a multigenerational study. Age of puberty acquisition, i.e., preputial separation (PPS) and vaginal opening (VO), was examined in male and female offspring, respectively. When compared to controls, a slight, but statistically significant delay in puberty acquisition was observed in females but not in males. WM-induced differences in the age at puberty acquisition were compared to those reported in S–D rats administered either a defined mixture (DM) of nine regulated DBPs or individual DBPs. Regression models were developed using individual animal data on age at PPS or VO from the DM study. Puberty acquisition data reported in the WM and individual DBP studies were then compared with the DM models. The delay in puberty acquisition observed in the WM-treated female rats could not be distinguished from delays predicted by the DM regression model, suggesting that the nine regulated DBPs in the DM might account for much of the delay observed in the WM. This method is applicable to mixtures of other types of chemicals and other endpoints.
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Several dihaloacetic acids alter intestinal microbial populations and their metabolism, which could lead to bioactivation of promutagens or procarcinogens in rats [26]. Dibromoacetic acid alters spermatogenesis and disrupts testicular steroidogenesis in male rats [27,28]. In addition, dibromoacetic acid disrupts estrous cyclicity and suppresses estradiol catabolism, which leads to alterations in steroid production in female rats [29,30].
Water disinfection greatly reduced the incidence of waterborne diseases, but the reaction between disinfectants and natural organic matter in water leads to the formation of drinking water disinfection by-products (DBPs). DBPs have been shown to be toxic, but their effects on the ovary are not well defined. This study tested the hypothesis that monohalogenated DBPs (chloroacetic acid, CAA; bromoacetic acid, BAA; iodoacetic acid, IAA) inhibit antral follicle growth and steroidogenesis in mouse ovarian follicles. Antral follicles were isolated and cultured with either vehicle or DBPs (0.25–1.00 mM of CAA; 2–15 μM of BAA or IAA) for 48 and 96 h. Follicle growth was measured every 24 h and the media were analyzed for estradiol levels at 96 h. Exposure to DBPs significantly inhibited antral follicle growth and reduced estradiol levels compared to controls. These data demonstrate that DBP exposure caused ovarian toxicity in vitro.

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^☆: This paper has been reviewed by the Health Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.

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Spermatotoxicity of dibromoacetic acid in rats after 14 daily exposures☆

Abstract

Toxicol Appl Pharmacol

Metabolism

Toxicol Appl Pharmacol

Fundam Appl Toxicol

Fundam Appl Toxicol

Fundam Appl Toxicol

Reprod Toxicol

Reprod Toxicol

Reprod Toxicol

Tissue Cell

Water disinfection: microbes versus molecules—an introduction of issues

Environ Health Perspect

Identity and yields of major halogenated products of aquatic fulvic acid chlorination

Environ Sci Technol

Chlorinated acids and chloral in drinking water

J Am Water Works Assoc

The occurrence of disinfection by products in US drinking water

J Am Water Works Assoc

Teratogenic activity of trichloroacetic acid in the rat

Teratology

Developmental toxicity of dichloroacetate in the rat

Teratology