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Transgenerational epigenetic effects of substance use
An epigenetic trait is a heritable phenotype arising from chromosomal changes in the absence of DNA sequence alterations. Epigenetic changes can occur over the lifetime of an individual, affecting their own gene expression, but can also occur in an individual's germline cells, transmitting modifications in gene expression to descendants. Lamarckian inheritance, which is the idea of transmitting acquired characteristics to progeny, had fallen out of favor prior to epigenetic understanding due to an inability to link environmental exposure to sequence changes in DNA. Many different modifications can be made to DNA without changing the sequence, such as methylation, acetylation, phosphorylation, in addition to histone modifications.

Transgenerational epigenetic inheritance occurs when epigenetic information is transferred through the germline in the absence of direct environmental exposure. Substance use has been tied to phenotypic effects in progeny, but many of these associations are due to use during pregnancy, altering the intrauterine environment directly. These are not considered to be truly transgenerational epigenetic effects, as the epigenetic changes would be due to direct exposure to the substance via maternal blood or environment, and not the transmission of epigenetic modifications in the germ cells. Fetal alcohol spectrum disorders are an example of this kind of phenotype. Transgenerational changes in epigenetics regarding pre-pregnancy parental behaviours of both sexes have recently been a focus of attention. It appears that age of onset, intensity, and duration of an individual's substance use behaviour can affect the epigenetic changes elicited in themselves and/or future generations. Association studies in humans and laboratory experiments using rodents have shown possible transgenerational epigenetic effects associated with the use of various substances.

Tobacco smoking
Smoking of tobacco has been associated with epigenetic changes of certain genes across the lifespan, with modifications varying depending on intensity and length of use, ethnicity, and the age of onset of the smoking behaviour. An analysis of maternal smoking effects has concluded that smoking during pregnancy was more responsible for observed effects in progeny than maternal smoking prior to pregnancy. It's been shown in rats that when females are exposed to nicotine neonatally or in utero, their offspring exhibited insulin resistance and increased blood pressure, despite not having been exposed to nicotine themselves. Paternal smoking in childhood (before the age of 11) has been linked to greater BMI in male, but not female, offspring.

Opiates
The use of prescription opiates by teenage girls has significantly increased since 2004. In rats, maternal adolescent opiate exposure changed offspring μ-opioid receptor (OPRM1) expression in the ventral tegmental area, with a more pronounced effect in male offspring. Offspring adults and their progeny also displayed sex-specific changes in social and emotional functioning, as well as altered responses to morphine. Male rats exposed to opiates in adolescence, when mated with unexposed females, had offspring with sex specific changes in adrenal weight, LH, and Hypothalamic B-endorphin.

Cannabis
In rats, a link has been shown between adolescents given THC and changes in dorsal striatum gene expression of progeny, resulting in an increased effort in heroin seeking.

Alcohol
Binge drinkingin adolescent rats has been shown to alter hypothalamic gene expression in progeny in the absence of fetal alcohol exposure. Differential effects on progeny based on their sex has been observed in paternal mice exposed to alcohol. This sex difference involved increased behavioural sensitivity and reduced alcohol drinking in sons but not daughters.

Cocaine
Outside of the brain, cocaine concentration is highest in the testes of male mice, where it can bind to spermatozoa, making paternal exposure effects on offspring hard to discern between direct exposure and transgenerational epigenetic effects in first generation progeny. Voluntary cocaine ingestion by rat fathers increased BDNF expression in the male, but not female, offspring Prefrontal cortex, resulting in a resistance to cocaine's reinforcing effects. Male offspring also had increased association of acetylated Histone H3 with BDNF promoters. DNA methyltransferase-1 expression was decreased in the seminiferous tubules of testis in rats that used cocaine; together with histone acetylation, this finding provides a possible mechanism for transgenerational epigenetic inheritance. Offspring of cocaine using fathers exhibited deteriorated attention and spatial working memory, particularly in female progeny. These findings corresponded to offspring of exposed mice, so direct exposure of sperm to cocaine may be causing these effects rather than heritable epigenetic changes.