UP researchers find environmental toxins poison epigenetic inheritance

In a study that signals potential reproductive and health complications in humans, now and for future generations, researchers at the University of Pretoria and Canada’s McGill University and Université Laval have concluded that toxins in the environment, notably DDT, modify the sperm epigenome at sites potentially transmitted to the embryo at conception.

The study reveals that men exposed to DDT may produce sperm that could have health consequences for their children. Epigenetic changes were found to occur in genes that are involved in fertility, embryo development, neurodevelopment and hormone regulation. These alterations correspond to the higher levels of birth defects and increased incidence of diseases, such as neurodevelopmental and metabolic diseases, that occur in DDT-exposed populations, including in Canada’s North.

While it is generally understood that women should avoid exposure to environmental contaminants because toxins make their way into the embryo, research on how a man’s exposure and his sperm might also be changed through the epigenome has been scant – that is, until the recent publication of an article titled ‘The Association between Long-Term DDT or DDE Exposures and an Altered Sperm Epigenome – a Cross-Sectional Study of Greenlandic Inuit and South African VhaVenda Men’ in the journal Environmental Health Perspectives.

Nearly two decades ago, the first research study using a rodent model showed that exposures to a toxicant endocrine-disrupting chemical altered the heritable layer of biochemical information in sperm, the epigenome.  This changed fertility and led to disease across rodent generations in unexposed animals. In the years following, millions of dollars have been poured into animal studies to better understand how such exposures can transmit disease through the epigenome across generations. These studies confirmed the phenomena known as “epigenetic inheritance”, whereby environmental exposures alter the sperm epigenome, a biochemical layer of information that controls how DNA is used to express genes during sperm production and in the developing embryo. This epigenetic control of gene use includes DNA methylation and histone proteins. Whether such exposures act similarly in humans was unknown.

“We identified regions of the sperm epigenome that are associated with the serum levels of DDE (chemicals that form when DDT breaks down); this association follows a dose-response trend, which is quite striking, in that, the more DDE you’re exposed to, the higher the chromatin or DNA methylation defects are in the sperm,” said Ariane Lismer, PhD, the study’s lead author, who completed the work while pursuing her PhD at McGill’s Department of Pharmacology and Therapeutics.

“Secondly, there was an enrichment of regions that were changed in sperm that are predicted to retain some of their chromatin marks in the pre-implantation embryo,” Lismer added. “That led us to think that these regions might escape epigenetic reprogramming and have a direct role in regulating embryo gene expression. So if they’re altered in sperm and they’re transmitted to the embryo, which is something that I’ve shown is possible in mice, the regions that are sensitive to DDE in sperm might be having an impact directly in the embryo.”

“We demonstrated that the sperm epigenome’s response to toxin exposures may be linked to disease in the next generation,” said Professor Sarah Kimmins, who led the research as a professor of pharmacology and therapeutics at McGill and is now a professor in the Department of Pathology and Cell Biology at Université de Montréal. “This is a critical new step for the field, because while there are many studies of animals demonstrating toxin effects on the sperm epigenome, studies in humans have not comprehensively demonstrated this.”

“Instinctively, it’s long been accepted that the environment is critical to child health and the well-being of the mother, because she carries the baby and she lactates, et cetera,” added study co-author Dr Janice Bailey,  formerly a professor of animal sciences at Université Laval and now Scientific Director at Fonds de Recherche du Québec en Nature et Technologies (FRQNT). “But men have been excluded from that equation. We tend to think that all they have to do is fertilise, but we forget that half of that genome and epigenome comes from the fathers, and half of it comes from the mothers. What that epigenome does in embryo development is critical for normal development.”

The decade-long research examined the impact of DDT on the sperm epigenome of South African VhaVenda and Greenlandic Inuit men. Despite the existence of the Stockholm Convention, a global treaty that aims to protect human health and the environment from the effects of persistent organic pollutants, the South African government has special permission to use DDT for malaria control.

“The use of DDT for indoor residual spraying for malaria vector control has been very controversial,” said Prof Tiaan de Jager, Dean of the Faculty of Health Sciences and a professor of environmental health at the University of Pretoria’s School of Health Systems and Public Health. “While most endemic provinces now use alternative chemicals, DDT is still used in some areas when needed.”

These pollutants can move across vast distances, from the southern hemisphere to the northern hemisphere, by way of the “grasshopper effect”. This means they evaporate with warm air and return to Earth with rain and snow in colder areas, where they persist in the Arctic food chain. With global warming, the exposure of human and animal populations to DDT is reportedly increasing.

“There’s a pressing need to find alternatives to malaria control and to put those in place, such as vaccines and alternative pesticides, because with this research, we’re showing that DDT is having an impact not only on the health of the exposed generation, but potentially on the next generation as well,” Prof Kimmins said.

South Africa is moving towards malaria elimination by introducing alternative strategies.

“While we, and other countries, still depend on the use of DDT, we should look at safer alternatives and be innovative in our approach to achieve elimination,” Prof De Jager said. “The reality is that people, especially young children and pregnant women, are still dying from malaria. We cannot afford for people in malaria-endemic regions to refuse spraying their houses, as it will increase their risk of getting malaria.”

“The scary part is that DDT is still out there,” said Dr Bailey. “It could have long-lasting effects on human health and development, but then there’s the other overall notion that irrespective of DDT, the environment itself affects both women and men.”

Although the study focuses on DDT exposures, Prof Kimmins says it is not a leap to suggest that exposures to more common household endocrine disruptors such as those found in cosmetics and personal care items may have a similar effect.

Researchers

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  Professor Tiaan de Jager

  Professor Tiaan de Jager is serving his second term as Dean of the Faculty of Health Sciences at the University of Pretoria (UP). He is a professor in Environmental Health at UP’s School of Health Systems and Public Health (SHSPH) and holds an Extraordinary Professorship in the section Andrology at the University’s Department of Urology, School of Medicine.
  
  Prof De Jager, who completed his undergraduate studies at Free State University, says his research interest was piqued in 1993 when he became a medical natural scientist at UP’s Department of Urology in the Faculty of Health Sciences and its academic partner Steve Biko Academic Hospital. His research career officially kicked off when he enrolled for a PhD in Reproductive Biology at UP in 1995.
  
  He is doing research at the University because it is a leading research institution that is not only graduating the leaders of tomorrow but has as its vision the creation of new knowledge with the aim of making a difference locally and globally. Prof De Jager says he is proud to be part of this visionary institution and fortunate to be able to lead and conduct research within this framework. “We focus our activities and contribution to making an impact on society above all else,” he says. “It is important to me that we graduate students who are not only good at their jobs and well educated, but who also understand that they have a responsibility to be life-changers and that they need to impact society and contribute positively to change in Africa.”
  
  The attainment of the 2030 Agenda for Sustainable Development Goals (SDGs) is a common thread throughout Prof De Jager’s research, which places a specific focus on SDG 3 (Good Health and Well-being). “My primary research focus is on male reproductive health, specifically related to environmental health and toxicology,” he explains. “I investigate the effects of environmental endocrine-disrupting chemicals (EDCs), including insecticides used for malaria vector control, such as dichlorodiphenyltrichloroethane (DDT), on male reproductive health.”
  The link between male reproductive health and malaria control has resulted in several international research projects that deal with the impact of malaria and associated malaria control on communities where the disease is prevalent, including South Africa, Botswana, Zimbabwe, Mozambique and Malawi. These novel research concepts are fed into safer malaria control strategies, which include drug discovery solutions; policy and regulatory framework intervention; prevention with public health partners; and education and awareness raising.
  
  Prof De Jager is the Director of the UP Institute for Sustainable Malaria Control (UP ISMC), which is a prime example of cross-faculty research. This transdisciplinary institute involves all nine UP faculties as well as the Gordon Institute of Business Science school. The UP ISMC coordinates and promotes collaborative research on safer, more sustainable malaria control and management strategies, generates new knowledge and supports new activities pertaining to safe malaria control in Africa.
  
  “Our interactions and collaborations, however, are not limited to the confines of UP, but includes partners from all spheres,” Prof De Jager says. “This includes communities, government, private industry, and international partners based at research institutions, higher education institutions and science councils.”
  
  As Director of the UP ISMC, Prof De Jager’s main agenda is researching and coordinating efforts to bring about sustained control, eventually leading to the elimination of malaria, starting in South Africa and extending to neighbouring countries like Botswana, Mozambique, Zimbabwe and Malawi.
  
  “Communities affected by malaria need to take responsibility for the control of mosquito vectors and the prevention of bites, while healthcare providers need to take responsibility for early-warning systems and treatment to alert communities to the presence of possible outbreaks,” says Prof De Jager.
  Vector control efficacy and malaria treatment services rely on the commitment of and buy-in from provincial and national governments, as poor communities are unable to carry the costs themselves.
  
  In South Africa, malaria is most prevalent in the Vhembe District in Limpopo. Here, malaria control policies rely on indoor residual spraying, using chemicals such as DDT and pyrethroids to control mosquito vectors. “Based on the evidence of the danger that DDT poses to both human (Bornman et al. 2018) and natural ecosystems, we have started developing and exploring alternative methods of control,” Prof De Jager explains. “In the Vhembe District, we have tested indoor polyethylene wall linings impregnated with long-lasting insecticides, with great success (Kruger et al. 2015), and in Botswana and Zimbabwe, we have field-tested the efficacy of microbial larvicides to control mosquito larvae (Mpofu et al. 2016). Both these methods have the potential to be effective if local communities are supported by municipal and provincial agencies based on sound research methodologies.”
  
  The institute has seen several highlights over the past few years, one of the most recent being a breakthrough in 2020 amid the challenges brought on by the COVID-19 pandemic. “We had a breakthrough relating to drug discovery, where we were trying to find compounds to block the parasite interaction,” Prof De Jager explains. “Our research group, under the lead of Prof Lyn-Marie Birkholtz along with local and international partners, focused their research on the parasite and found specific drug compounds that can be effectively used as part of an intervention. This is a major breakthrough in terms of our malaria research.”
  
  Other highlights span a longer period; a few noteworthy examples include the UP ISMC being designated as one of three South African Medical Research Council-collaborating centres for malaria research in the country; the UP ISMC being host to the DSI/NRF SARChI Chair on Sustainable Malaria Control (Prof Birkholtz); and the institute being named winner of the Communication for Outreach and Creating Awareness of SET and Innovation Award at the 2017/2018 NSTF-South32 Awards.
  
  Some of Prof De Jager’s personal research highlights include successfully graduating several postgraduate students. Also, many of his students have won awards at the annual Faculty Research Day where their research projects were presented. His appointment as an expert peer reviewer of the World Health Organisation’s (WHO) ‘Global assessment of the state of the science of endocrine disruptors’ document was another highlight, as was his appointment by the National Minister of Health to the South African Malaria Elimination Committee.
  
  Over the past 18 months, Prof De Jager says he has dedicated his time to further developing and growing the UP ISMC, with the long-term aim of malaria control and elimination. Various experts and role players from UP and government are currently involved. “The UP ISMC is developing safer alternatives for malaria control, including chemical product design/development, which includes WHO Phase II and III Field Trials on new patents for malaria vector control [Prof Walter Focke, Chemical Engineering], health impact/toxicology/health risk [Prof Riana Bornman, SHSPH, who Prof De Jager credits as his research mentor] and integrated vector management/decision tools and policy [Dr Clifford Mutero, SHSPH and Duke University].
  
  “To take this into the future, and using opportunities created by big data sciences, we have introduced an initiative using remote sensing for malaria control (ReSMaCA) in collaboration with the French and South African national space agencies (CNES and SANSA), and national, regional and other international researchers. This approach takes climate change into account when developing early-warning systems for malaria. The programme will focus on environmental and climate issues, and will include vector and parasite control strategies, with a strong focus on cross-border malaria transmission. With funding from the German Research Foundation, we are also working on assessing the controlled release of volatile mosquito repellents from nanostructured polymers to reduce infectious tropical diseases including malaria. These initiatives focus on innovative approaches to malaria elimination in the African region and will involve researchers from developing countries facilitating capacity building and contributing towards the development of the African continent.”
  
  Prof De Jager adds that an international project on malaria insecticides and reproductive health, funded by the Canadian Institutes of Health Research, laid the foundation for projects in Chiapas in Mexico, Quebec City, Canada, and later in Limpopo, further driving his special interest in malaria-related research.
  
  His research agenda will continue to focus on questions related to the SDGs, particularly on EDCs, malaria control and the environment. “My passion is to continue being a life-changer through my contribution to research, making a difference in society and battling for a better life for our vulnerable, poor communities.”
  

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  Professor Riana Bornman

  Professor Riana Borman’s research seeks to understand the effects of endocrine-disrupting chemicals (EDCs) on human and environmental health, with a special focus on male reproduction. Most of her research is carried out in the rural areas of the Vhembe District in Limpopo, in communities where insecticide is sprayed to control malaria-carrying mosquitoes.
  She began her career in the Department of Urology at the University of Pretoria (UP) in 1980 and had a research topic to explore within the first week, which triggered a career-long curiosity. “I am still researching the role of EDCs on human health today,” she says.
  
  Prof Bornman, who obtained an MBChB at UP, says her research focus developed from her experiences in managing patients in clinical settings. “As a clinical physician, I realised that human and environmental health was intricately affected by environmental pollution, especially exposure to EDCs. Being a clinician at UP has created unique opportunities to conduct research in the Limpopo province.”
  
  Her field of research addresses the unintentional health consequences of annual indoor residual spraying of insecticides to control malaria-carrying mosquitoes. In the Vhembe District, dichlorodiphenyltrichloroethane (DDT) is sprayed to control these mosquitoes and reduce cases of malaria and death. While DDT is largely a banned chemical, according to the Stockholm Convention on Persistent Organic Pollutants, it is allowed in some countries, including South Africa, for malaria vector control.
  But there is growing concern around the adverse health effects associated with DDT. Scientific evidence from South Africa is crucial and contributes to the body of evidence that is calling for safer alternatives to DDT for malaria vector control.
  
  The chemical is effective for about six months and needs to be sprayed every year. Prof Bornman’s research shows that annual spraying has negative, long-term consequences for pregnant women and young children. “We are seeing these consequences in children, possibly persisting into future generations, suggesting long-term health effects. Our research collects important irrefutable scientific evidence of the health impacts of EDCs in communities exposed to insecticides.”
  
  Prof Bornman is the co-principal investigator for the Venda Health Examination of Mothers, Babies and the Environment (VHEMBE) study, which is being conducted in collaboration with Prof Brenda Eskenazi of the University of California, Berkeley in the US and Dr Jonathan Chevrier of McGill University, Canada. The VHEMBE study is the first birth cohort from a population that is currently exposed to DDT via annual spraying and is the biggest longitudinal birth cohort from Africa. The study group recruited and enrolled 752 mother-child pairs at Tshilidzini Hospital in Thohoyandou and have monitored the children up to eight and a half years of age for various possible health impacts.
  
  She hopes to continue doing research that contributes to improving the health of those whose voices are not often heard.
  
  She is also co-principal investigator and clinical leader of the South African Prostate Cancer Study, which is investigating the genomics of prostate cancer in African men; this is being done in partnership with Prof Vanessa Hayes, Scientific Director of the Garvan Institute of Medical Research in Sydney, Australia. A recent highlight in their research work has been funding awards from major international bodies to investigate the development of aggressive prostate cancer in black African men. “We are extremely motivated to continue with this research,” says Prof Bornman. “Successful awards reflect that the scientific leaders in our field support our approach.”
  
  Over the past 18 months, the prostrate cancer study group began a new project that focuses on the mutational signatures of DDT and the possible role of this EDC on prostate cancer aetiology. Prof Bornman is also the study leader for a new study on knowledge, attitudes and practices of traditional healers, primary healthcare service providers and men in the rural Vhembe District.
  
  She says in her research work she was inspired by Prof Dion du Plessis, former Head of Urology and Dean of the Faculty of Health Sciences at UP, who taught her to think beyond the obvious, to dream big and to just DO it!
  Her academic role model was Prof Carl Franz, former Head of Surgery at UP. He was a prime example of how to integrate laboratory and clinical medicine in an academic career, she says.
  
  Her message to school learners or undergraduates who are interested in her field is: “Every one of us, irrespective of our discipline, can make a difference in the lives of people. My research aims to improve the lives of people living with the constant threat of malaria under unforgiving environmental and socio-economic conditions. We can all do research that makes a difference. One just has to care enough about people.”
  
  Her hobbies are photography and travel.
  
  
  

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  Dr Sean Patrick

  Dr Sean Patrick is a senior lecturer in the Health Measurement Sciences Division at the School of Health Systems and Public Health (SHSPH) at the University of Pretoria.

  He is a scientist in the Environmental Chemical Pollution and Health (ECPH) Research Unit, and a member of the management committee of the University of Pretoria Institute for Sustainable Malaria Control (UP ISMC).

  His research on Endocrine Disruptors has led him to explore transdisciplinary approaches to health, merging the fields of Public Health, Engineering, and the Built Environment. He initiated a study to understand the complexities of environmental endocrine disruptor exposure and its interaction with living spaces, with the goal of developing a community resilience strategy using engineering monitoring tools.

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  Dr Natalie Aneck-Hahn

  Dr Natalie Aneck-Hahn has been in the field of Andrology for more than 26 years and is the Deputy Director Medical Natural Sciences in the Department of Urology and head of Andrology at the Steve Academic Hospital. She is also the Director of the Environmental Chemical Pollution and Health (ECPH) Research Unit at the School of Health Systems and Public Health at the University of Pretoria.

  Dr Aneck-Hahn’s research focus is on the effect of endocrine disrupting chemicals on male
  reproductive health and in the environment. She has authored and co-authored several technical reports
  and peer reviewed publications.

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