This document discusses emerging concepts in autism research, focusing on the potential roles of germline exposures and heritable epigenetic effects. It notes the dramatic surge in autism cases and outlines current thinking on genetic and environmental contributions. However, it argues that the field has overlooked the possibility of germline mutations or epigenetic alterations caused by parental exposures that could contribute to autism in offspring. The document examines evidence that prenatal exposures like medications, cigarette smoke, and other toxins during critical windows of germline development may cause heritable effects through mutagenesis or epigenetic mechanisms. It calls for further research on transgenerational transmission of environmentally-induced autism phenotypes from germline exposures.

1. Old Exposures, Heritable Effects, and
Emerging Concepts for Autism Research
Jill Escher, MA, JD
@JillEscher
for AutismEscher Fund
Humans start as molecules
G e r m l i n e E x p o s u r e s . o r g
OUT OF THE PAST:

2. “WHAT EPIDEMIC? IT’S JUST
NATURAL NEURODIVERSITY AND
SHIFTING DIAGNOSTICS”
Autism is just a
“strange gift” handed
down through millions of
years of evolution.
Wrong!

3. DRAMATIC SURGE IN SERIOUSLY
DISABLING AUTISM CASES
Calif. Department of Developmental Services
Autism Cases by BirthYear 1943-2010

4. WHAT’S CAUSING AUTISM?
GENES
100s of genes contribute—about 10% of
cases can be attributed to known
genomic errors, 10% more forecast
ENVIRONMENT
Exogenous factors—ie, prematurity,
certain drugs, maybe 20%
UNKNOWN
Probably at least 60% of cases, but
strong evidence of heritability
60% 20%
10%
10%

5. ARE WE ASKING THE RIGHT QUESTIONS?
Genes or environment?
How about genes and environment?

6. MUTAGENESIS: HETEROGENOUS DE NOVO
MUTATIONS FOUND IN AUTISM
Yuen et al 2015: 69% of the affected siblings carried different ASD-
relevant mutations.
Brandler et al 2016: “We propose that genetic risk for ASD is attributable
to an elevated frequency of gene-disrupting de novo SVs.”
Iossifov et al 2015: Supports theory that 'ultra-rare' mutations of vulnerable
genes may play causal role in roughly half of ASD cases.

7. EPIMUTAGENESIS: EXPOSURES CAN
ALTER HOW GENES WORK
Hormone mimics/
endocrine disruptors
Industrial chemicals
Nutrition
(eg, vitamins, folate,
famine)
Acute stress
Drugs and
pharmaceuticals
Cigarette smoke
Plasticizers
Epigenetics: “Heritable changes in gene expression caused by
mechanisms other than alterations to underlying DNA sequence.”
Pesticides
Radiation
Exercise

8. Methylation
Chemical tags on DNA.
Histone modification
Chemical tags on DNA
structural proteins.
Lab of Moshe Szyf
“Don’t bother
transcribing this gene.”
“This gene is open for
business!”
EPIGENETIC FACTORS CAN UP-REGULATE
OR DOWN-REGULATE GENE EXPRESSION
ncRNAs
Can regulate gene
output
May carry environmental
info via gametes
For example:

9. EXPOSURES CAN ALTER SOMATIC GENE
EXPRESSION
Thalidomide
DES
(Diethylstilbestrol)
Fetal Alcohol
Syndrome

10. IN UTERO EXPOSURES CAN ALTER GERMLINE, TOO,
THROUGH MUTAGENESIS OR EPIMUTAGENESIS
F0 = Mother
F1 = Fetus
F2 = Germ cells / grandchildren
A highly vulnerable phase for the F2s.

11. “CRITICAL WINDOW” OF
FETAL GERMLINE DEVELOPMENT
Primordial
germ cells
DNA de-methylation and
re-methylation: Period of
dynamic and vulnerable
epigenetic reprogramming

12. GENES ARE JUST A PART OF “HERITABILITY”
• Protein-coding genes (exome) represent only 1.5% of genome.
• Most of the genome is about transcription and regulation.
• And on top of that, a wide variety of epigenetic processes,
including imprinting.
• Brain development depends
on subtle control of gene
expression, dosage and timing,
not just Mendellian “genetics.”

13. DO GERMLINE EXPOSURES MATTER?
MY STORY WOULD SUGGEST YES
Son, 17 Daughter, 10
I was born in 1965 in Los Angeles.
I have three beautiful, genetically normal children
from three low-risk, normal pregnancies.
Yet two of my children are severely
neurodevelopmentally disabled, nonverbal
autistic, will need lifelong 24/7 1:1 care.

14. In 2010, I obtained my
mother’s 1965 obstetric
records. What did they mean?
In 2011, I discovered I had been a
subject in a study (Reinisch 1977)
examining fetal effects of synthetic
steroid hormone drugs.
In 2013, I obtained records from
the Kinsey Institute detailing my
prenatal drug exposures.
A TRIO OF UNEXPECTED DISCOVERIES
1. 2. 3.

15. Progestins, estrogens, corticosteroids. Why? “To prevent miscarriage.”
“Mad Men” era of maternal medicine. Such drugging was common.
0
225
450
675
900
Pre 1 2 3 4 5 6 7 8 9
Progestin (Deladroxate)
Estrogens (Estradiol)
Corticosteroids (Prednisolone)
Progestin (Deluteval [Delalutin])
Clomiphene
Pergonal
Mg of drug
My month of gestation in 1965
Roughly equivalent to 20-30,000 birth
control pills’ worth of synthetic steroids.}
WHAT WERE MY EXPOSURES?

16. Example: Joan Hutchens was also exposed prenatally
to an “anti-miscarriage” hormone regimen in 1965.
Three of her five children have idiopathic autism.
We started as
eggs when our
mom was a fetus.
I’M NOT ALONE:
MANY OTHERS SHARE MY STORY

17. PREGNANT WOMEN WERE HEAVILY
MEDICATED IN THE POST-WAR DECADES
Synthetic hormones Sedatives, barbiturates Anti-nausea drugs Amphetamines

18. LET’S NOT FORGET OTHER EXPOSURES
Pesticides (eg, DDT) Agent Orange (dioxin)
Flame retardants
(eg, PBDEs)
PCBs
Plasticizers
(eg, BPA, phthalates)
Air pollution Radiation

19. PREGNANCY SMOKING WAS COMMON
0
8.5
17
25.5
34
1955 1970 1990 2010
Smoking prevalence
among US females
Cigarette smoke =
mutagenic and
epimutagenic
components
Doctors sometimes
recommended it as an
appetite suppressant
Placenta from a tobacco-
exposed pregnancy

20. Ammonia
Arsenic
Benzene
Benzo(a)pyrene
Carbon monoxide
DDT/pesticides
Formaldehyde
Hydrogen cyanide
Nicotine
Radiation
Tar
TOXIC COMPONENTS OF CIGARETTES
(Short list)

21. IN ASD, GRANDMATERNAL PREGNANCY
SMOKING WAS COMMONLY REPORTED
Yes, these are anecdotes but they may raise important questions
about potential germline mutagenesis or epimutagenesis.
Families had no history of autism. Sampling of the F1 interviewees’ F2’s:

22. 1. High prevalence, compared to other gestational toxicants
2. Acute levels (eg, 5,400 cigarettes for a pack-a-day pregnant smoker)
3. Ease of ascertainment, compared to other gestational toxicants
4. High toxicity: known mutagenic and epimutagenic compounds
5. F1 somatic DNA damage and pathology: exposure known to raise risks of
epimutation, disease and birth defects
6. F1 germline damage demonstrated (molecular, anatomical)
7. F2 pathology demonstrated (eg, Bhide, Rehan)
WHY WE SHOULD LOOK FOR F2 EFFECTS
OF GRANDMATERNAL SMOKING

23. AUTISM RESEARCH TODAY
1 2
Toxic
Exposures
Germline
Damage
Root Cause Molecular
Pathway
Brain
Differences
Phenotypes Interven-
tions
During
critical
windows
Disruption
to germline
or early
embryo
Heritable
errors in
early cells;
or proximal
fetal
exposures.
Impaired
molecular
pathways
Abnormal
neurodevel-
opment and
function
Communi-
cation,
social,
behavioral
deficits
Biological or
behavioral
treatments
“Genetics First”

24. WHERE I THINK RESEARCH NEEDS TO GO
1 2 3 4 5 6 7
Toxic
Exposures
Germline
Damage
Mutation /
Epimutation
Impaired
neurons
Brain
Differences
Phenotypes Interven-
tions
During
critical
windows of
germline
synthesis
Disruption
to germline
or early
embryo
Heritable
errors in
early cells
Impaired
molecular
pathways
Abnormal
neurodevel-
opment and
function
Communica
tion, social,
behavioral
deficits
Biological or
behavioral
treatments
Toxicology Genetic
Toxicology /
Mutagenesis
Genetics Neurobiology Neuroscience Psychology/
neurology /
psychiatry
Therapy /
Medicine

25. FSU, AHEAD OF THE CURVE
“We suggest that transgenerational transmission is a
plausible mechanism for propagation of environmentally
induced ADHD phenotypes in the population.”

26. “What the public must recognize is that mankind’s
most vital asset is not its material wealth but
its germ plasm—the very stuff of life.
“Since the germinal cells are what determine the health,
intellectual capacity, and all the other prime attributes of
future generations, everything possible must be done to
protect those—humanity’s most precious possessions.”
—Geneticist James Neel, 1969
OUR MOST VITAL ASSET

27. Webinar Series
LEARN MORE AT GERMLINEEXPOSURES.ORG