Multigenerational and transgenerational effects of paternal exposure to drugs of abuse on behavioral and neural function

Abstract

Addictions are highly heritable disorders, with heritability estimates ranging from 39% to 72%. Multiple studies suggest a link between paternal drug abuse and addiction in their children. However, patterns of inheritance cannot be explained purely by Mendelian genetic mechanisms. Exposure to drugs of abuse results in epigenetic changes that may be passed on through the germline. This mechanism of epigenetic transgenerational inheritance may provide a link between paternal drug exposure and addiction susceptibility in the offspring. Recent studies have begun to investigate the effect of paternal drug exposure on behavioral and neurobiological phenotypes in offspring of drug-exposed fathers in rodent models. This review aims to discuss behavioral and neural effects of paternal exposure to alcohol, cocaine, opioids, and nicotine. Although a special focus will be on addiction-relevant behaviors, additional behavioral effects including cognition, anxiety, and depressive-like behaviors will be discussed.

Paternal morphine self-administration produces object recognition memory deficits in female, but not male offspring

“…Naïve male Sprague Dawley rats self-administered either morphine or saline 3 hours per day, for 60 consecutive days. The germline epigenome is an essential carrier of environmental information across generations (Bale 2015;Goldberg and Gould 2018;Pierce et al 2018;Yohn et al 2015). Methylation of DNA and the action of small non-coding RNAs can be transmitted through the father's sperm to his offspring and play an essential role in neurodevelopmental programming (Jenkins and Carrell 2012).…”

“…Exposure to drugs of abuse changes several components of the epigenetic landscape, including acetylation of histones and DNA methylation in sperm of both rodents (Le et al 2017;Vassoler et al 2013) and humans (Chorbov et al 2011). Paternal drug exposure causes disruptions in a multitude of behaviors, including drug sensitivity and reward, anxiety, and memory in offspring (Goldberg and Gould 2018;Pierce et al 2018;Vassoler et al 2018a;Yaw et al 2019;Yaw et al 2018;Yohn et al 2015). Paternal cocaine exposure produced increased anxiety in offspring whether cocaine was experimenteradministered (Fischer et al 2017) or self-administered by the sires (White et al 2016).…”

Intergenerational Effects of Alcohol: A Review of Paternal Preconception Ethanol Exposure Studies and Epigenetic Mechanisms in the Male Germline

“…Thus, to test the hypotheses inspired by cross‐generational epidemiological data, preclinical investigators have utilized isogenic rodent strains under controlled laboratory conditions to directly test the effects of various paternal preconception exposures to a vast range of environmental insults on an equally expansive number of biological and behavioral measures in offspring. Most prominently featuring studies pertaining to dietary change, chronic stress, and various drugs of abuse, many paternal preconception exposures with rodents have now been found to directly impart complex physiological and behavioral phenotypes to offspring (for excellent reviews, see Rando and Simmons, , Chang et al., ; Goldberg and Gould, ). For instance, obese fathers confer deficits in glucose metabolism to offspring (Chen et al., ; Cropley et al., ; de Castro Barbosa et al., ; Fullston et al., ).…”

Addiction in focus: molecular mechanisms, model systems, circuit maps, risk prediction and the quest for effective interventions

“…A genetic mechanism may be another (risk) candidate as suggested by a review that converged primarily on the role of nicotinic cholinergic receptor subunits, and other neurotransmitter systems as well as nicotine metabolism enzymes, to understand the various stages of nicotine addiction; interestingly, studies on the heritability of smoking initiation demonstrate substantial evidence for gene–environment interaction, although the precise molecular genetic mechanism(s) remains unknown (Sharp & Chen, ). Another thought provoking approach highlights the effect of paternal drug exposure to alcohol, cocaine, opioids and nicotine on behavioural and neurobiological phenotypes in the offspring in rodent models, with a special focus on addiction‐relevant behaviours, but also cognition, anxiety and depressive‐like behaviours (Goldberg & Gould, ). These authors invoke epigenetic changes that may be passed on through the germline, whereby this mechanism of epigenetic transgenerational inheritance may provide a link between paternal drug exposure and addiction susceptibility in the offspring.…”