As someone who works in epigenetics and has colleagues working on transgenerational inheritance, this article gets some stuff right, but it's also obvious that there are large gaps in the author's reading of the literature, which biases the interpretation of the field. I'd be happy to get specific if there's interest but I thought the larger readership should caveat emptor

Expand full comment
Jan 17, 2023Liked by Metacelsus

i'm super busy at the moment but I will get back to you on this as soon as I can

Expand full comment
Jan 14, 2023·edited Jan 14, 2023Author

I'd be happy to correct the post if you can point out these gaps. I'm a reproductive/germ cell biologist, not a specialist in inheritance.

Expand full comment

There's a bit of "deck stacking" in this post, as I see no reason to limit your discussion to mammals as these studies have notoriously low sample sizes and an inability to control for genetic variation. So I don't find the lack of evidence of TGI in mammalian studies to be evidence that epigenetic inheritance is somehow "less important" than other factors that may contribute to variation. besides the mechanisms involved (physio/mol) are ancient.

Expand full comment

most early research on transgenerational effects look at ”soft inheritance”, and included a wide range of biological phenomena such as maternal effects or the physiology of plasticity.

one of the earliest studies in TGI (FUJII T Nature 1978 vol: 273 "Inherited disorders in the regulation of serum calcium in rats raised form parathyroidectomised mothers (5659) pp: 236-238). This particular study looked at the transgenerational effects of parathyroid gland removal up to F3 offspring:

the authors unknowingly designed their experiment to show a truly “transgenerational epigenetic” mode of inheritance. They were more interested in studying parathyroid and thyroid function in rats, and discovered a transgenerational effect of parathyroid removal in gestating mothers. See Fig1 from that paper which goes out to F3.

Other types of early transgenerational experiments looked at

Effects across only one generation

Effects transmitted only through maternal or paternal sources

Effects of transgenerational exposure on all generations (cumulative carryover)

Maternal/paternal effects to several generations

Continuous exposure to stressors/chemicals or change in parental behaviors/phenotypes that affect offspring fitness

Likely different mechanisms

”carryover effects”

As you can see these studies weren't truly “transgenerational” and often used continued exposures across generations (cumulative carryover effects) or only taken out to F2s (not getting at epigenetic mechanisms)

Expand full comment

Modern TGE experiments are shaped by our understanding of epigenetic programming. I recommend Randy L. Jirtle & Michael K. Skinner Nature Reviews Genetics  (2007) and looking at Figure 6: A model for endocrine-disruptor-induced epigenetic transgenerational disease

Example from this paper:

1. Germ cells in gonad undergo re-methylation during fetal gonadal sex determination

2. During gonadal sex determination, fetal testis has steroid receptors and is a susceptible target for endocrine agents

3. Altered steroidal/endocrine activity during gonadal sex determination could cause altered re-methylation patterns in germ cells

Exposing gestating rats to estrogenic/antiandrogenic endocrine disruptors during fetal gonadal sex determination caused reduced fertility in F1 male rates

Expand full comment

another paper:

Anway et al. Science (2005). This study investigated a transgenerational phenotype after vinclozolin treatment of F0 gestating rats. measuring multiple phenotypes out to F4.

Beyond mammals we have access to larger sample sizes

Bhandari et al. Scientific Reports (2015)

Fish embryos were exposed during critical period of germ cell development/male sex determination. The treatment was BPA the group measured transgenerational phenotypes starting at F2, then F3 and F4. F2 had reduced fertilization. F3s developed from fertilized eggs from F2 parents had reduced survival as did F4.

Another paper: Baker et al. Toxicological Science (2014). The cool thing about this paper is that it shows how different experimental designs examine potentially different mechanisms of transgenerational effects.

Outside of developmental toxicology (my area) we have the famous

Agrawal et al. Nature (1999) paper on daphnia "Transgenerational Induction of Defenses in animals and plants.

So that's my 2 cents: )

I agree with this blog (or whatever) post that many studies of adaptive transgenerational effects are actually “transgenerational plasticity” or generalized term for maternal effects.

Expand full comment

Thanks for the info about this. I also saw a recent paper in Cell that induced epigenetic inheritance in mice (which I now linked at the top of this post). I plan to write an update (part 4 of the epigenetics series) that covers that paper, and in the update I will also mention the information you provided here. I'm hoping to write that update within the next 2 months, although my research might get in the way somewhat.

I don't dispute that epigenetic inheritance is important for non-mammalian species. This post focused on mammals since humans are mammals and I've seen a lot of people making claims about epigenetic inheritance in humans that aren't well-supported.

Expand full comment

I look forward to it. Humans are indeed mammals, and they are also vertebrates which are animals, which are multicellular and so on and so forth. Remember foundational genetics was conducted mainly in yeast, fly, worm and grasshopper (chromosomes). The model organism suitable for the questions being asked is really all that matters here, don't you agree?

Expand full comment

As someone who's not a biologist, I'm interested in hearing your views on this topic!

Expand full comment