I blame my parents

     We’ve all been somewhat scarred by our parents at some point in our lives, whether by seeing pictures of them in their 80’s workout clothes or catching them smooching in the kitchen. But what if even before we were born, even before we were thought of, the actions of our parents changed our destiny?  We all understand that our DNA gets passed down from generation to generation and results in us having blue eyes or brown hair or large foreheads, but often it’s a little more complicated than that. Our DNA makeup is consistent in every cell of our body, however each cell type requires the expression of only a certain number and kind of genes. This can be mediated through epigenetic mechanisms that suppress or turn on certain genes without changing the actual DNA structure. DNA methylation is a prime mechanism in epigenetics where a methyl group (three hydrogen atoms bound to a carbon atom) prevents a transcription factor from binding to DNA resulting in the suppression of that gene. Through our lives we need to express and suppress different genes and this can be due to changes in our DNA methylation patterns. But most amazingly, patterns of DNA methylation can be modified in response to our environment allowing for the expression of genes that are beneficial in that setting while suppressing others that are not. This phenotypic plasticity depends on the presence of genes that allow for the expression of a certain adaptive phenotype as well environmental cues that trigger the epigenetic modifications involved [1]. 

    Phenotypic plasticity ranges widely between species, allowing female stoplight parrotfish to undergo sex reveral in order to replace absent males [2] and for padomorphic amphibians to retain juvenile or larval characteristics while dedicating resources to sexual development and reproduction when presented with certain hostile environments [3]. Phenotypic plasticity allows for organisms to adapt to their environmental conditions, however there is often a trade-off. Early investment in growth by the common frog due to unfavorable hatching conditions can present itself later in life as a disadvantage in reproduction or a shortened span [4]. Many epigenetic changes can be in response to current environmental situations and can eventually be reserved[1]. However, it's common for epigenetic changes to become permanent fixtures in the organism’s genetic and phenotypic make up. Although these adaptations may have been beneficial in a certain setting they may be unnecessary in others, using energy sources that could be used elsewhere. 

But how do the experiences and phenotypic changes of the parent affect the offspring?

It’s common knowledge that women shouldn’t smoke or drink or do drugs while pregnant. And this makes sense, these substances can cross the placental barrier inhibiting proper growth or leading to fetal addiction. But then there are unintentional exposures during pregnancy that result in direct and indirect genetic and chemical changes. There are carcinogens we are subjected to regularly, such as many processed meat, that may cause mutations in DNA resulting in tumor growths [5]. There are also endocrine disrupting agents such as synthetic estrogens that mimic hormones or prevent natural hormones from binding to their receptor sites. And so often, these substances require such small concentrations (think one particle of toxicant in a billion particles of water) to have a dramatic impact on the endocrine system. And much of what we come in contact with can be one or either of these.  For example, In the early to mid 1950’s, thousands of pregnant women were prescribed thalidomine to prevent morning sickness and nausea. It wasn’t until 1962 when the connection was made between limb abnormalities in offspring and the administration to thalidomine to pregnant mothers [6]. The authors of the book “Our Stolen Future”, Colborn, Dumanoski, and Myers aptly named these substances as “hand-me-down poisons”. 

But exposure during pregnancy is not the only way that chemicals can be passed down to the next generation.  A lifetime exposure of small concentrations of harmful substances can also directly or indirectly cause damage in offspring. A study published in 2021, resulted in changed behaviors in only male offspring guppies when parents were chronically exposed to low doses of commonly prescribed ADHD medicine, Ritalin [7]. And it’s not just the mothers who are to blame. A 2020 study showed that chronic exposure in male lab mice to bisphenol A (BPA), a common industrial chemical, resulted in impaired glucose tolerance and impaired insulin secretion in female offspring [8] . The mechanisms and routes of transgenerational effects vary widely and are often not understudied. Often it is indirect effects of passed down contaminants that result in negative phenotypic expression in offspring. For example, parental zebrafish exposure to environmental toxicant, TDCIPP, led to DNA methylation in offspring resulting in downregulation in neuronal cell bodies [9]. These modifications in offspring phenotype can be directly linked to parental lifetime exposures and environmental conditions.

Now our parents themselves aren’t solely to blame, yes they got so bored in the days before computers and smartphones that they might have licked a few walls, but at the time lead-based paint was a common household item. And doctors lauded the miracle estrogen supplement, diethylstilbestrol or DES, administered to pregnant mothers as being able to prevent miscarriages and premature births. However, decades later it was discovered that the daughters of DES exposed mothers themselves faced fertility issues later on in life [6]. In fact, we can’t even let our grandparents off the hook, because it's not just substances and DNA mutations that can be passed down. Epigenetic modifications and phenotypic conditions from parents or even grandparents can be inherited. Organisms can integrate environmental cues from not only their environments but from those environments of generations before them. Epigenetic inheritance is widely misunderstood but is thought to be the result of transfer of parental epigenetic traits during certain critical fetal developmental stages [10]. And these transgenerational effects can result in the expression of adaptive or harmful phenotypes in offspring. A long-term study conducted by the Umeå University in Sweden and the Avon Longitudinal Study of Parents and Childhood at Bristol University in England has found a connection between grandchild lifespan and food scarcity in parental grandparents [11].  Additionally, a study conducted on moths revealed that poor food quality in parental lifetime resulted in immunosuppression in offspring [12]. And the studies tend to go on and on, however this field is still in its infancy. We often observe outcomes but have yet to fully understand the mechanisms behind each phenomenon. But the moral of the story is that next time you want to blame your parents, make sure to also blame your grandparents, old timey doctors,  lead based paint, and most definitely blame DNA methylation. 

References:

[1] Bonamour Suzanne, Chevin Luis-Miguel, Charmantier Anne and Teplitsky Céline (2019) Phenotypic plasticity in response to climate change: the importance of cue variationPhil. Trans. R. Soc. B3742018017

[2] J.R. Cardwell, N.R. Liley (1991) Hormonal control of sex and color change in the stoplight parrotfish, Sparisoma viride. General and Comparative Endocrinology, 81: 7-20

[3] Bonnett, R.M., Steffen, M.A., Lambert, S.M., Wiens, J.J. & Chippindale, P.T. (2014) Evolution of paedomorphosis in plethodontid salamanders: ecological correlates and re-evolution of metamorphosis. Evolution 68 (2): 466–482.

[4]   Pablo Burraco, Ana Elisa Valdés, Germán Orizaola (2020) Metabolic costs of altered growth trajectories across life transitions in amphibians. Journal of Animal Ecology 89:855–866.

[5] José L. Domingo, Martí Nadal (2017) Carcinogenicity of consumption of red meat and processed meat: A review of scientific news since the IARC decision,Food and Chemical Toxicology,105: 256-261

[6] Colborn, Theo, Dianne Dumanoski, and John P. Myers. Our Stolen Future: Are We Threatening Our Fertility, Intelligence, and Survival? : a Scientific Detective Story. , 1996. Print.

[7] De Serrano, A.R., Hughes, K.A. & Rodd, F.H. (2021) Paternal exposure to a common pharmaceutical (Ritalin) has transgenerational effects on the behaviour of Trinidadian guppies. Sci Rep 11, 3985. https://doi.org/10.1038/s41598-021-83448-x

[8] Cetewayo S. Rashid, Amita Bansal, Clementina Mesaros, Marisa S. Bartolomei, Rebecca A. Simmons (2020) Paternal bisphenol A exposure in mice impairs glucose tolerance in female offspring, Food and Chemical Toxicology, 145: ISSN 0278-6915,

[9] Xisheng Ding, Wen Sun, Lili Dai, Chunsheng Liu, Qian Sun, Jianghua Wang, Panwei Zhang, Kun Li, Liqin Yu (2020) Parental exposure to environmental concentrations of tris(1,3-dichloro-2-propyl)phosphate induces abnormal DNA methylation and behavioral changes in F1 zebrafish larvae,Environmental Pollution, 267:ISSN 0269-7491

[10] McRae, A.F., Powell, J.E., Henders, A.K. et al. Contribution of genetic variation to transgenerational inheritance of DNA methylation. Genome Biol 15: https://doi.org/10.1186/gb-2014-15-5-r73

[11] Marcus E. Pembrey (2010) Male-line transgenerational responses in humans, Human Fertility, 13:4, 268-271, DOI: 10.3109/14647273.2010.524721

[12] Triggs, A.M. and Knell, R.J. (2012), Parental diet has strong transgenerational effects on offspring immunity. Funct Ecol, 26: 1409-1417