Rats that had ancestors who had been exposed to a fungicide experienced health problems. Credit: Kseniia Glazkova/Alamy
Exposure to a fungicide induced changes to gene expression in rats that persisted for at least 20 generations. It also increased the chance of offspring developing kidney disease, obesity or experiencing complications when giving birth, according to the longest-running study1 of ‘epigenetic’ changes in mammals.
Evidence is accumulating that environmental exposures, such as to chemicals, can induce heritable changes that do not alter an organism’s DNA. These tweaks to the chemical markers on the DNA occur in germ cells, which are then passed on to future generations. But most studies have focused on directly exposed generations rather than subsequent generations.
The latest study, by Michael Skinner, who studies epigenetic inheritence at Washington State University in Pullman, and his colleagues, studied the effect of exposing an initial generation of rats to the fungicide vinclozolin on 20 subsequent generations. The researchers found that the rats that had ancestral exposure had higher rates of sperm cell death and an increase in problems giving birth, including maternal and offspring death, compared with the 12th and earlier generations or non-exposed rats.
The findings are “quite shocking”, says Anthony Hannan, an epigenetics researcher at the Florey Institute of Neuroscience and Mental Health in Melbourne, Australia.
However, the implications for people are less clear. Although the passing down of epigenetic changes through generations has been shown in people — the descendants of children conceived during a famine have an increased risks of diabetes, for instance — more work is needed to determine whether people are affected by specific conditions that their ancestors were exposed to, adds Hannan.
Still, the findings are a warning that society needs to be more careful about air pollution and the kinds of chemicals that are permitted to be released into the environment, says Razia Zakarya, an epigenetics researcher at the University of Technology Sydney, Australia. “It is quite alarming to see this sort of accumulation of epigenetic markers can then lead to pathology so late down the line,” she adds.
The use of vinclozolin as a fungicide on food crops has declined over the past 25 years and is banned in several countries, such as Australia and those in the European Union.
Indirect exposure
Skinner and his colleagues started the experiments in 20172. They injected pregnant rats with vinclozolin and a solvent called DMSO, then bred those rats with non-exposed rats for 23 generations — the equivalent of at least 500 years in people, says Skinner. The first pregnant rat, its offspring and its grand offspring were considered to be directly exposed, and subsequent 20 generations were ancestrally exposed. The control group was injected with DMSO and bred for four generations1.
The team used next-generation sequencing to identify regions in the rats’ genomes in which there were differences in methylation, or the addition of a methyl group to DNA. They found that later generations of rats had more regions with differences in methylation compared with controls, showing that the epigenetic changes persist across multiple generations.
When they looked at the rats’ kidneys, prostate, testis and ovaries, the researchers found that the rate of diseases affecting these organs increased over subsequent generations. In the twentieth generation since the initial exposure, for example, all 11 rats exposed through their paternal lineage had ovarian abnormalities compared with 11 of the 19 control rats. The team also observed more severe disease in the exposed rats, such as obesity and kidney disease. They argued that DNA methylation disrupts normal organ development and function.
They also report higher rates of the rats experiencing abnormalities while giving birth, including death of the mother in labour or of the pups in utero, in ancestrally exposed female rats and non-exposed female rats bred to ancestrally exposed males. Between 20% and 70% of births were unsuccessful in later generations.
