Impact of nicotine, alcohol, and cocaine exposure on germline integrity and epigenome

Abstract

Converging evidence suggests that parental exposure to drugs of abuse can affect offspring phenotypes. The impacts of drug abuse on germ cell quality may mediate multigenerational and transgenerational inheritance, although biological pathways underlying this mode of inheritance are not yet characterized. Germline epigenetic marks are modified by drug exposure and have emerged as promising mechanistic candidates in recent work. Drug exposure also impacts overall germline integrity and reproductive functioning, although the role of these consequences in multi/transgenerational inheritance is unclear. This review synthesizes literature on effects of exposure to alcohol, cocaine, and nicotine on the germline with a focus on epigenetic modifications following drug exposure and broader impacts on germline integrity and reproductive functioning. We discuss potential interactions between reproductive functioning, germline integrity, and germline epigenome/transcriptome in pathways underlying multi/transgenerational inheritance. We find that existing data may support independent or interactive contributions of these germline impacts on offspring phenotypes in a manner that may mediate multi/transgenerational inheritance.

FIGURE 1

Left: Maternal founder multi/transgenerational inheritance in the female line Exposure occurs during the lifetime of the F0 generation (white mouse). The F1 generation (blue fetus) and its developing germline (orange germline), which produces the F2 generation, are also exposed. The F1 generation gestates the F2 generation (orange fetus), whose germline (green germline) produces the F3 generation. Multigenerational phenotyping begins in the F2 generation (orange mouse), which is derived from the originally exposed F1 germline (blue fetus, orange germline). Transgenerational phenotyping begins in the F3 generation (green mouse), which is the first that had no direct contact (via gestation or germline) with the original exposure. Note that the original exposure need not necessarily occur during F0 gestation (F0 pregnancy with F1), as any exposure prior to pregnancy may chronically alter uterine environment or other pregnancy parameters consequential to F1 development. Right: Paternal founder multi/transgenerational inheritance in the male line Exposure occurs during the lifetime of the F0 generation (white mouse), also directly exposing the F0 germline (blue germline), which produces the F1 generation. Multigenerational inheritance begins in the F1 generation (blue mouse), which is derived from the originally exposed F0 germline. The F1 germline (green germline), which produces the F2 generation, never contacts the original exposure. Thus, transgenerational phenotyping begins in the F2 generation. Non-color accessibility image description: Left side, top = white mouse, blue fetus, orange germline; Left side, second to top = Blue mouse, orange fetus, green germline; Left side, third to top = orange mouse, green fetus; Left side, bottom = green mouse; Right side, top = white mouse, blue germline; Right side, middle = blue mouse, green germline; Right side, bottom = green mouse.

FIGURE 2:

Theoretical biological pathways underlying multi/transgenerational inheritance: 1) Additive model of germline impacts downstream of drug exposure, wherein changes in reproductive functioning, germline integrity, and/or germline epigenome additively mediate multi/transgenerational inheritance; 2) Sequential model of germline impacts downstream of drug exposure, wherein changes in reproductive functioning cause altered germline integrity, which then triggers germline epigenomic modifications that mediate multi/transgenerational inheritance; 3) & 4) Alternative sequential models, wherein impacts of drug exposure on one or more, but not all, of the discussed factors in sequence are sufficient to produce multi/transgenerational phenotypes; 5) and 6) Pathways depicting a single independent mediator of multi/transgenerational inheritance in drug exposure models.