Profound Impact of Teratogen-Induced Birth Defects:

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21st century concerns and promises

A Birth Defects Insights Blog

By Madhumita Basu, PhD, MS, Nationwide Children’s Hospital

“Not every birth defect is associated with something we can do to prevent it. But those we can prevent, we should.” — Dr. Hema DeSilva.

I recently came across a striking statistic reported by Christopher Flavelle in his New York Times article on June 18th, 2020. Reviewing 68 studies which include more than 32 million births in the United States, investigators in this issue of JAMA Netw Open. 2020;3(6): e208243; doi:10.1001/jamanetworkopen.2020.8243 have reported that 48 studies on air pollutants and 9 studies on heat exposure had significant association with adverse birth outcomes. These metadata revealed that environmental perturbations exacerbated by air pollutants have a direct consequence on the health of pregnant women, with such exposures being more likely to result in infants who are premature, underweight, or stillborn. Notably, studies that have examined fine particulate matter (PM2.5) found a consistent positive association with preterm birth and low birth weight. Because pregnant women are at higher risk of altered cardiopulmonary physiology by air pollutants and other environmental teratogens, it is absolutely critical to understand the impacts of climate change on pregnancy outcomes at all gestational ages.

The association between maternal exposure to teratogens and an increased occurrence of structural birth defects has been recognized for almost 60 years now. Some of the seminal works from Josef Warkany, Harold Kalter, James G. Wilson, James J Nora and many other investigators in the early to mid-1960’s have recognized that, apart from genetic risk factors, maternal environment plays a vital role in fetal development and congenital malformations. Even with this long-standing literature and existing public health guidelines, continuing efforts have been made to prevent teratogen-induced birth defects. Presently, we agree that the challenges of studying key molecular events underlying human birth defects are two-fold. First, the ethical concern of human fetal tissue research and second, the pleotropic nature of a teratogen.

A recent news feature article in Nature, September 2021 issue by Kendall Powell has addressed a 14-day rule, first proposed in 1979 as a limit on how long after fertilization human embryos can be grown in culture (Nature. 2021 Sep;597(7874):22–24). This 14-day rule was firmly established in the research community based on the time when the primitive streak (a structure that marks the point at which the embryo sets up the body axes) first appears in the embryo, i.e., shortly before gastrulation, which

begins around 14 days in humans. In May 2021, the International Society for Stem Cell Research (ISSCR) released a new set of guidelines that relaxed this 14-day rule, allowing developmental biologists to study gastrulation to understand the mechanisms of cell differentiation into specialized tissues and organs (Lovell-Badge, R. et al. Stem Cell Rep. 16, 1398–1408 (2021)). The relaxation of the 14-day rule empowers researchers to study lab-grown human embryos post-fertilization. These revised guidelines permit researchers to better understand the important stages of human embryo development and enable scientists to learn origins of birth defects and why some pregnancies fail. I would encourage the early career birth defect researchers and developmental toxicologists to be aware of the huge possibilities ahead of us. The breadth of data likely to be obtained from human fetal tissue research after “lifting restrictions” (generated responsibly and thoughtfully), human induced pluripotent stem cell derived cells, and transgenic animal models would certainly facilitate better understanding of disease causation and might mitigate certain birth defects.

The other challenge of birth defects research is tissue or cell-type specific responses to a particular teratogen at different developmental stages. The dose, duration, and timing of fetal exposures to teratogens underlies the spectrum and degree of malformations crucial in determining the complex responses to exposure. Many of the maternal environmental and metabolic perturbations acting in prenatal life continue to have long-term consequences and compromise the quality of an offspring’s life. One such example is an increased risk of childhood cancer in those with congenital heart disease, suggesting a shared developmental origin for the diseases (Birth Defects Res. 2018 Oct 16;110(17):1314–1321). Although I have highlighted one specific example here, the implications of such correlations are huge; further investigation is needed to elucidate the multifactorial etiology of developmental origins of disease. I am a firm believer of basic scientific research and think that, by amalgamating the knowledge of clinical association between teratogenic exposure and birth defects with targeted disease modelling in rodent models (in vivo), in specialized cell lines (in vitro, hiPSCs) and using a systemic approach (in silico), we could better manage adverse pregnancy outcomes and fetal phenotypes. Till date, teratogen-induced birth defects are categorized as; 1) Physical teratogens (ionizing agents, hyperthermia); 2) Metabolic conditions (diabetes, obesity, malnutrition, thyroid disorders, phenylketonuria); 3) Maternal Infections (e.g., rubella virus, herpes simplex virus, Zika virus, and syphilis); and 4) Chemical and drug exposures (e.g., alcohol, tobacco, organic mercury compounds, polychlorinated biphenyls, as well as some pesticides/herbicides, industrial solvents, prescription and over the counter drugs, and illicit and recreational drugs). Due to impacts of the climate crisis discussed earlier and living amidst a global pandemic for last two years, unfortunately this list is rapidly expanding. Studies have reported higher rates of unfavorable birth outcomes in women infected with SARS-CoV-2 in late pregnancy (Am J Obstet Gynecol MFM. 2020; 2:100107). While these association studies are preliminary in nature, there is an urgent need to continue monitoring long-term implications of the clinical cases of COVID-19 infection during the first and early second trimester of pregnancy. This will certainly advance our understanding linking the role of COVID-19 on fetal and postnatal development (J Glob Health. 2020 Dec; 10(2): 020378).

Independent studies across the world have indicated that there are several considerations in determining the type and amount of damage to the developing fetus resulting from exposure to a particular teratogen or combination of more than one teratogen (Berger, 2005). https://ilearn.laccd.edu/courses/133116/pages/harm-to-fetus-teratogens. This warrants more careful study design to address the nature of perturbations in the maternal-fetal interface before we define “exposome (maternal exposures)-phenome (fetal phenotype) association.” The precise mechanism(s) through which the intrauterine environment may impact various cell types in the fetus, during development, is not clear. With rapid advancements in single cell sequencing technologies, bioinformatics analysis, and multi-species data integration, investigators are now capable of cataloging the teratogenic impact on individual cell types; for example, during heart, brain, and limb development. Single cell and spatial multi-omics platforms will serve as important tools for advancing the field of Birth Defects Research. For example, Cao et al. (Science. 2020 Nov 13;370(6518): eaba7721) used a total of 5 million cells to catalogue the single cell atlases of both gene expression and chromatin accessibility in 121 human fetal tissues representing 15 organs. This research serves as a rich resource for the exploration of human gene expression in diverse tissues and cell types. These studies are of utmost significance for understanding fetal development in a “normal maternal environment” and should be considered before embarking on research projects dissecting the mis-regulation of genes following teratogenic exposure. In closing, birth defects do affect society, the healthcare system and, most importantly, families with children who have such defects in many different ways. Therefore, we have social responsibility and need to act now! Global, multicentric, interdisciplinary measures should be undertaken to create human birth defect atlases similar to one mentioned above. Utilizing all the knowledge we accumulate, we should be able to better manage the pediatric patients with teratogen-induced birth defects.

About the Author

Madhumita Basu, PhD, MS is a Principal Investigator at the Center for Cardiovascular Research in Nationwide Children’s Hospital and Research Assistant Professor at the Department of Pediatrics, The Ohio State University College of Medicine. She joined Nationwide Children’s Hospital in 2013. Madhumita’s research is mainly focused on understanding the key molecular mechanism(s) of abnormal embryonic heart development when exposed to pre-existing maternal diabetic environment, which contribute to elevated risk of congenital heart defects.

More about the Society for Birth Defects Research and Prevention (BDRP)

To understand and prevent birth defects and disorders of developmental and reproductive origin, BDRP promotes multi-disciplinary research and exchange of ideas; communicates information to health professionals, decision-makers, and the public; and provides education and training.

Scientists interested in or already involved in research related to topics mentioned in this blog are encouraged to join BDRP and/or attend or present their research at the Society’s 62nd Annual Meeting this summer. BDRP is the premier source for cutting-edge research and authoritative information related to birth defects and developmentally mediated disorders. Our members include those specializing in cell and molecular biology, developmental biology and toxicology, reproduction and endocrinology, epidemiology, nutritional biochemistry, and genetics, as well as the clinical disciplines of prenatal medicine, pediatrics, obstetrics, neonatology, medical genetics, and teratogen risk counseling. In addition, BDRP publishes the scientific journal, Birth Defects Research. Learn more at http://www.birthdefectsresearch.org. Find BDRP on LinkedIn, Facebook, Twitter and YouTube.

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