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Published on: September 15, 2012
Alterations in the reproductive patterns of female mice exposed to xenobiotics
J B Bishop1, R W Morris, J C Seely
1National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Abstract:
Chemicals, by virtue of their varied interactions with biological molecules, are expected to differ in the way they may alter female reproduction. Reproductive toxicity may reflect effects either on the female germ cells or on various maternal processes such as ovulation, implantation, pregnancy, and parturition. In either case, the ultimate manifestation of chemical toxicity on female reproduction is a decrease in the number of normal young born. Very little information is available on the effects of chemicals that are nonhormonal in nature on the long-term ability of treated females to produce offspring. This report presents the results of long-term female total reproductive capacity (TRC) tests on 29 chemicals, including pharmaceuticals, pesticides, and alkylating and industrial agents. For each chemical, the minimum test involved an evaluation of the maximum tolerated dose administered as a single intraperitoneal injection. Females were single-pair mated with an untreated male for most of the female's reproductive life span (a minimum of 347 days posttreatment) and scored for the number of live births produced during this period. Confirmatory dominant lethal experiments or histological examinations for numbers of small follicles were carried out when mutagenic effects or cytotoxicity, respectively, were suspected as the basis for reduced fertility. Of the 29 chemicals studied, 17 had reproductive effects which may be grouped into one of three classes: (1) those that reduced the total number of young and litters per female, (2) those that reduced the total number of young but not of litters, and (3) those that had no significant effect on the total number of young produced but reduced the size of the first and/or second litters. The TRC provides a capacity for detecting a range of toxic insults upon female reproduction. Many of the chemicals were indeed shown to affect the reproductive performance of females through mutagenic and/or cytotoxic effects on follicles. In some cases, however, no causative mechanism could be identified for the observed reduction in reproductive performance. Nevertheless, with this report the number of chemicals tested by this TRC procedure has been quadrupled and the categories of chemicals tested have been substantially broadened.
Insights
This study evaluated 29 chemicals for their long-term effects on female reproduction using total reproductive capacity (TRC) tests. Seventeen chemicals demonstrated reproductive toxicity, impacting fertility through mutagenic or cytotoxic effects on germ cells and maternal processes.
Area of Science:
- Toxicology
- Reproductive Biology
- Environmental Health
Background:
- Chemicals can impact female reproduction through germ cell or maternal process disruption.
- Limited data exists on non-hormonal chemical effects on long-term female fertility.
- Reproductive toxicity is ultimately measured by reduced offspring viability.
Purpose of the Study:
- To assess the long-term reproductive capacity of female rodents exposed to 29 diverse chemicals.
- To identify and categorize reproductive toxicants affecting female fertility.
- To evaluate the utility of the total reproductive capacity (TRC) test for detecting reproductive insults.
Main Methods:
- Administered maximum tolerated dose of 29 chemicals (pharmaceuticals, pesticides, industrial agents) via intraperitoneal injection.
- Single-pair mated females with untreated males for a minimum of 347 days post-treatment.
- Scored live births, with confirmatory dominant lethal assays or follicle histology for suspected mutagenicity or cytotoxicity.
Main Results:
- Seventeen of 29 chemicals exhibited reproductive effects, categorized by impact on litter/young counts or litter size.
- Mutagenic and/or cytotoxic effects on follicles were identified as mechanisms for reduced fertility in many cases.
- Some chemicals caused reduced reproductive performance without an identifiable causative mechanism.
Conclusions:
- The total reproductive capacity (TRC) test effectively detects a range of chemical-induced reproductive toxicity in females.
- A significant number of tested chemicals negatively impacted female reproductive performance.
- The study broadened the scope of chemicals assessed by the TRC method, enhancing its utility.
